EEE Positron Emission Tomography of Striatal Serotonin Transporters in Parkinson Disease Levente Kerenyi, MD; George A. Ricaurte, MD, PhD; David J. Schretlen, PhD; Una McCann, MD; Jozsef Varga, PAD; William B. Mathews, PhD; Hayden T. Ravert, PhD; Robert F. Dannals, PhD; John Hilton, PhD; Dean F. Wong, MD, PhD: Zsolt Szabo, MD, PhD Background: Lite is known about serotonin neurons in Parkinson disease (PD) Objectives To study the serotonin system in PD with, positron emission tomography, using the serotonin trans- porter radioligand [!*C](+)MeN5652. Design and Patients: We measured the density of the serotonin transporter and the density of [\C]WIN35428- labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To as- sess the ellects of possible differences in blood flow oF brain atrophy, we also measured regional cerebral blood flow and the size of the regions of interest for the cau- date nucleus and putamen, Results: Patients with PD showed reductions inthe spe- cific distribution volumes of "C](+)MeN5652 inthe eau- date (P<.01) and putamen (P<.01), along with the ex- pected reductions in striatal ["'C]WIN35 428 binding, (P<01). There were no reductions in regional cerebral blood flow or the sizes of the regions of interest, mil galing against potential confounding elfects of blood flow. brain atrophy, or partial volume effects. Reductions in serotonin transporter binding correlated with ratings of disease staging. Conelustons: These results suggest that the density of| serotonin transporters, like that of dopamine transport- ers, is reduced in the striatum of patients with PD and that these changes are related to disease stage “Arch Neurol. 2003;60:1223-1229 ARKINSON DISEASE (PD) is high specificity and selectivity for the SERT From the Department of Neurology; Medal School Debrecen (Dr Keren) Department of Nuclear ‘Medicine, Universit of Debrecen (Dr Varga, Debrecen, Hungary; the Department of Radiology, Johns Hopkins Medical Institutions (Drs Rcaurte, Ravert,Dannal Hilton, Wong, and Szabo), Baltimore Md: the Department (of Psychiatry and Behavioral ‘Sciences, Schoo of Medicine (Dr Schrtln and McCann), «and the Division of Nulear ‘Medicine (Dr Mathews), Jolns Hopkins University, Baltimore (aepnnyreD) ARCH NETROUVOL a SEPT characterized by a progee sive loss of neurons in subcor- tical monoaminergic nuclet, particularly those in the sub- slantia nigra." Both in vitro” and in vivo”® studies have yielded extensive evidence of reduced dopamine (DA) innervation in the brains of patients with PD. In contrast, rla- tively line is presently known about the st tus of brain serotonin (5-HT) neurons in PD." Further, the clinical significance of S-HT changes observed thus far in post- ‘mortem studies is largely unknown.” With modern brain imaging, it isnow ossible to selectively image neuron sys- {ems of interest in the living human brain. Various investigators have used ['21]B- CIT with single-photon emission com- puted tomography (SPECT) to visualize siriatal DA innervation and midbrain sero- tonin transporter (SERT) density simulta- neously.""» For the present studies, ['tpbeta-CIT was not ideal because i pret erentially labels the DA transporter (DAT) rather than the SERT in the striatum. Re- cently, ["C](4)MeN5652, a positron emis- sion tomography (PET) radioligand with (©2003 American Med jamanetvrork.com/ on 01/21/2022 has been developed." The distribution of [C]G)MeNS052 correlates well with the known distribution of the SERT in hu- ‘mans, and yieldsa reliable assessment of SERT binding in brains with a docu- ‘mented loss of 5-H innervation." The aim of tis study was to assess the status of striatal 5-HIT innervation in living patients with PD, using [?°C](+)McN3652 and PET. In particular, we sought to: (1) evaluate SERT binding in the striatuin in PD patients; (2) explore the relationship be- ‘ween changes in the SERT and DAT in pa tients with PD; (3) determine whether al- cations in the SERT of DAT in patients with PD are related to alterations in r gional cerebral blood flow; and (4) dete: ‘mine if changes in the SERT and DAT cor- relate with clinical stages of PD. Ls} STUDY PARTICIPANTS A total of 26 subjects participated in the study 1S adults with idiopathic PD and 13 normal controls (NCs). Patents ranged in age from 54 1 Association, All rights reserved.1075 years (means, 65.247 yea) hd completed 13 824.2 Year of education, and inladed @ men and'7 women. Pax tents with PD were recruited from the Johns Hopkins Bay- ‘ew Medical Center Movement Disorder cis (Balmore, MA), Irhere the diagnosis of diopahic FD was made based onthe lina erterideseried by Hagheset al” Insdaliion, 13 NC ‘who ranged in age from 38 070 eats (ran sSD, 63 08113 Year) had completed 13.8424 years ofedaton, and ine ded 7 men snl women, parpated nthe stay ‘All of the PD patents and NC were administered he Hamilion Rating Sek for Depesion’*and the stactured Clin Cal Interview forthe Diagnesticand Statistical Manual of Men: tal Disorders, Fourth Eaton” None ofthe patients or contra Sbjct thought io have major pression, dementia, ct rent alcohol abuse or any other Axis I mental disorder. Any participant who carned a score of se than 24/50 onthe Mini Stent State Examination” was excluded. Al the patients tndrvent ettelogi sl physta caminatots, Discesing- ing wae aes with the Hchn-Yar Sale (V5) On this basis, 5 patients were rated as being in stage 1,4 sage 22 instoge3yand’instge 4. Disease severity asseatd whe most patients (12 of 15) wet taking antiparkinsonian mediation, fas determined using the Unied Parkinson's Disease Rating Sole" Fialy each psentcompltedaselraing eal of come petence for activities of daily living.” Twelve af the 13 par tents with PD were eeiving reament with | or more ant perkineonian medications at ndy entry, patie wax drug hive: Medications inched levodopaeabidopa (n=7)sele= filine (n=) and pamsipexl (m=2) None ofthe patients had taken any mediation fora least 12 hours belore the PET tay No patipants wer ig medications Known wo ease t= sistentaltertions inthe density ofthe SERT or DAT. The study ‘as approved bythe Johns Hopkins Univesity institutional e- ‘cw board, and al subject gave wit informed consent fo participate IMAGING PROCEDURES ‘Toensur the reproducbiliy of postioning forthe PET su tesa custom-made face matk wa ited to each participants head and attached tothe head-holder during magnetic reso- tance imaging (MRI) snd PET. Magnetic resonance imaging ‘vas performed o position the subjees head and delineate the Feglons of interest (ROW) using a GE Signa 3-T scanner (GE Medical Systems, Milwaukee, Wis)" ‘During each PET sessional participants received 3 injec- tions, Lith [°C] COMeNSOS2, Lith [¥CWIN 35428, and 1 ‘wth [PO]H.O, The average injected dose and spect acy tras 19 mCi (703 Mig) and 6800 mCi/umol (51600 MB Fimo) for F*C]()MN 3052, and 19 mc (703 MBq) and 4700 mevfimol (173900 MBigtma) for ["C]WIN 35488, The n- {ected dose for [°OIH,O was 75 mCi (2775 Mx). A GE so96PIas Whole Body PET Scanner was sed for imaging and 1 smut taneous slices, spaced 6.3mm aa, were acquired. The rans {hal plain) resolution was 94 my ull wth a af an tum), with an average axial resolution of 6 um Cll width at Hall maximum) in the center ofthe lel of view. A transmis sion scan was oblained witha 10-mCi(370-MBq) "Ge" pin Source for 10 mines and was used or altenatlon correction ofthe PET images. First, the WIN35428 tracer wa injected [MoTH.0 was injected afer the first study ended. ["c]Cs) ‘McN5052 was injected 30 minutes after the end ofthe [?OH.0 sy Tightcen serial dynamic PET images were acquired after the [HE]G@)MENSOSE injection was given during 93 min- utes" Seventeen PET scans were obtained during 2 75- timate nection with ["C]WIN 35428, after the ["OFL.Oin- jection, 41 seria PET images were acquired in 300 seconds. (aePnnyeD) ARCH NETROUVOL a SEPT (©2003 American Med ‘Downloaded From: https:/jamanetwork.com/ on 01/21/2022 After both the ("C]{+)MeN5052 and ["C]WIN 35428 injec tions, arterial blood samples were drawn manually to oblain theinput function for compartment analysis. The input unc- tion was corrected for metabolized radioligand activity" ‘Aer the [PO]H,0 injection arterial blood was drawn from the radial artery using an automated blood sampler pump and propelled through a coincidence counting device cross Calibrated with the PET scanner, To determine time activity Curves from ROls, PET and MRI fmages were converted (0 NetCDF/MINC format” (hup/fvarw bic mnt mcglcafsolwate Frsinefnine him; corepsration was achieved with he Auto- tated Image Registration algorithm software package.” Re- {lon of interest were drawn onasingleslice which wasselecied Based onthe judgment that it contained the best representa tin of that particular brain are, Regions of intrest were drawn, forthe fllowing brat regions: head of caudate, putamen, cer- chellum (Figure 1), snd haan (not shown). WIN33428 and McNS052 images were coregisterd using the same MRI im age The same ROts were usel for both racers and fitng was checked visually cach cae by cosplay ofthe PET and MRI images with the RO Staal binding of [\CIWIN35428 was expressed by the Roveerebellum ste activity ratio between 3 and 73 min- tts ater injection. ["€])MeN3052 binding ws quantified vith the apparent) toll dstbution volume tht was derived froma -compartment parameter model" The dsibution volume of specific binding (DV,) was calculated a=" DV, (DV. DVAVDV,., where DV, cis the radioligand distribu. tion volume in the cerebellum’ Using the PET seas ofthe [POIHO study, regional erebral lod low was calculated from {issue activity curves derived using the same ROl a forthe radioligand studies, Before fiting these tse curves, the a terial input function was corrected for bolus delay and disper STATISTICAL ANALYSIS ‘The primary hypothesis ofthe sty was that patients with PD would have significant reductions nthe DAT and SERT con red with age- and sex-matched NCs_ A secondary hypoth- Cis was that reductions in the DAT and SERT would be post tively correlated with the stage of illness (HYS). Prior to hypothesis testing, {ests Were conducted be- tween the PD and NC groups on the following variable: age year cation: Mint Mental State Examination scores and the mean numberof voxels inthe various RO, To test the i= tnary hypothesis that sinital DAT and SERT binding ar re diced in PD, analyses of covariance were conducted, covary- ing for age. A probably of P05 was st asthe cael for statistical sigieance, witha correction for mulple et vai ables to contol fora ype | error” Pearson correlation analy ses were used lo assess relationships between disease severly and SERT and/or DAT binding Dataare give as meanasD unt les otherwise indicated TO }- The PD and NC groups did not differ significantly with respect 10 age (P=.58), years of education (Mini-Mental State Examination score, 28.14 1.6; P=.57), oF se Uuibution. Figure 1 shows ROls derived from MRIs to coregister with PET imaging. Comparisons revealed that the patients with PD and the NCs did not differ in the sizes of their respective caudate nuclei (1.19 4.20 vs 1.1440.19 mL), putamen (2.16 £34 vs 2.2540.27 mL), or cerebellum (10.1241.84 vs 10.344.L73 mL) (all P val ues >.10). Thus, the PD patients did not demonstrate 1 Association, All rights reserved.Downloaded From: https: a (a Figure 4. Rios of in issue te activity cares. The upper images show the RO ol he ce evidence of atrophic cha of the MRI measurements, yes in these structures on any ['C1(4)MeN5052 BINDING Binding of [!C](+)MeN5052 was reduced in the eau- date of subjects with PD (Fable 1 and Figure 2). The distribution volume of the cerebellum, used to assess non- specific binding of [!C](+)McN3052, was not statist- cally different between NCs and PD patients (NC 21.047.0; PD, 18.443.9; F P=.12), and the co- variance effect of age on cerebellar distribution volume was not significant (P=2.23; P=.15). The hypothesized reduction of the SERT in the striatum of patients with PD, as measured by ["C distri- 4+) MeN5052 bindiny bution volume of specific binding ‘was compa a P value of .04, adjusted for multiple comparisons and correlations.” The covariance effect of age was not sig nificant (P=0.173; P=.68), but the difference jamanetwork.comy/ on 01/21/2022 ae re et (Os) superimposed on aistrad pasion amission tomography and magatic resonance maging scan used for aculation lum. Tne er mages show te lef tei and eat and ih and eh he NCs (1.39208: caudate SERT density was sig and PD patients (0.60.40.30) in the icant (P=7.97; P=.01 Similarly, in the pustamen, the dist ribution volume of spe cific binding of ["C](+)McN3052 was reduced in PD pa sents (NC: 1,500.58; PD:0.9820.31; P=7.52; P=.01 with no significant covariance effect of ag 52: P=.23) (Table 1), Unlike DAT disproportionately reduced in striatal nuclei contralat eral to the more affected side of the body among PD pa- all P values SERT binding was not ents with asymmetric tremor oF rigidity 5). There was also a trend for reduced SERT binding {im the thalami (NC: 1.1540.69; PD: 0.8920.35): ever, the difference did not reach the expected level of P. significance [EC] WIN35 428 BINDING The binding of {*'C]WIN35428 to the DAT was tested by the general gnosis as a refer linear model using diSerotonin and Dopamine Transporter Binding Inthe Caudate and Putamen Among Patients With Parkinson Disease (PD) and Normal Controls (NC)* ea Pt Tneymewoese caudate javeg 0eoe030 797 Puumen 150458 0962031 75201 Penns as Cauéste 0770878" 240620554 7 007 Punmen 48940734 2100-061 389 <001 Datare gun as ean + SD ules herve inated. Data were snajed by fhe qnaa near mode contling forte covarance tet of es "Base on comet or mulpe parameters and parameter onlin, Pals le than 4 were cansiead sigan. ‘ence variable and the eaudate-cerchellumn ratio of pula men-cercbellum ratio as a test variable while control- ling for age. Even thouigh the age effect was significant in both the caudate (F=15.5; P2.001) and the putamen (£=103; P<.001), after controlling for age, PD patients showed lower caudate and putamen [!C]WIN35 428, binding than NCs. The putamen-cerebellum DAT bind- ing ratio was reduced by 30% (F=8.7; P=.007), and the ‘eauidate-cerehelluim DAT binding ratio was reduced by 20% (F=38.0; P<.001) in PD patients compared with NCs. Both differences are significant Of the 15 patients with PD, 10 had asymmetric tremor or rigidity (6, rightleft; 4, lel>right), When the ratios of DAT binding were compared for these sub- ‘groups, patients showed a 34% greater reduction in DAT binding in the putamen region contralateral to the most alfected side of the body, and 6% greater reduction in DAT binding in the caudate region contralateral to the most affected side of the body. This asymmetry in DAT bind- ing was significant only for the putamen (P=.006) (CORRELATION BETWEEN [¥C(+)MeN5052 AND ["'C]WIN35428 BINDING. The hypothesis that reductions in DAT and SERT bind- ing would corzclate with a more advanced stage of ill- ness was tested by the Spearman corzelation ofthe bind- ing of these ligands in the putamen (part ofthe striatum that is more affected in PD than the caudate nucleus) with the HYS. In dhe 13 PD patients, ['C])MeN5052 demonstrated a negative cortelation with HYS (r==0.57; P=.04) and a positive correlation with ['C]WIN35428 binding (1r=0.57; P=.04). The correlation between [MC]G)MeNM5652 binding and [!C]WIN35428 bind- ing was even more signilicant when NCs and PD patients were combined (1=0.58; P=.002) (Figure 3) AAs expected, the corzelation of ['C]WIN35428 binding With HYS was negative (7-062) (P=.02). No correla tion was found between the binding parameters of both radioligands with the Unified Parkinson's Disease Rating Seale and activities of daily living (all P values >-03), although the correlations between the clinical scores on HYS, the Unified Parkinson's Disease Rating Seale, and activities of daily living were all significant (r=0.84-0.02;, P<001). (aepnnyeD) ARCH NETROUNOL GE SES (©2003 American Med jamanetvrork.com/ on 01/21/2022 CEREBRAL BLOOD FLOW AND LIGAND UPTAKE Striatal cerebral blood flow did not differ significantly be- tween NCs and PD patients (43.146.9 vs 49.147.6 ml/ 100 g per minute, respectively; P>.05). Similarly, the group differences inthe ligand uptake parameter, K,, were not significant in the caudate (PD: 0.2940.05 mL/mL. of tissue; NC: 0.2040.06 mL/mL of tissue; P=.78 for main elect; P=-99 for covariance effect of age) and putamen (PD:0.35.20.05 mL/mL of tissue; NC: 0.3540.07 mL/mL, of tissue; P=.92 for main effect of age), —1kIinmm—_@y_§__ (Our results indicate that patients with PD have reduced specific distribution volumes of "C](+)MeNS652 in the caudate and putamen, along with the expected redue- tion in striatal [!'C]WIN35428 binding. Further, no r ductions in regional cerebral blood flow or the sizes of 97 for covariance effect the various ROIs were observed in PD patients, mitigat- {ing against potential confounding effects of blood flow. brain atrophy, and partial volume averaging, Taken to- gether, these findings suggest that the density of SERTs, similar to the density of DATs, is reduced in the stria- tum of patients with PD, presumably reflecting the loss, of serotonergle and dopaminerge innervation, respe- Patients with PD showed the expected decrease in DAT binding im the striatum. These results are in agres ‘ment with other studies wherein DAT binding decreases in PD have been found to range from 20% to 50% in the caudate and from 40% to 70% in the putamen." Nota- bly, patients with asymmetric tremor or rigidity showed 34% greater decrease in DAT binding in the putamen region contralateral to the most clinically affected side of| the body, which is also similar to earlier reports." Also con- sistent with earlier reports,» we found that reductions {mstrital DAT binding correlated with more advanced dis- case, as measured by the HYS, The present study extends these findings by providing preliminary evidence that re- ductions in striatal SERT binding also correlate with dis- case stage. Given the small number of subjects included in the analysis (n=13), additional studies will be neces- sary to reach definitive conclusions in this regard. A potential drawback of the neuroimaging mel ods we employed was the use of ['C](+)MeN5052,a PET radioligand that demonstrates considerable nonspecific binding even in the striatumn, Nonspecific binding could minimize the assessed contrast between the 2 groups of subjects and result in an underestimation of dillerences. The effect of nonspecific binding was minimized, using the cerebellum as a reference region, Normalization in- cluded both subtraction of and division by the cerebel- lar distribution volume of striatal total distribution vol- lume values, attempting to account for effects of both parameter bias and variance. Although minimal but mes- Surable specific binding in the cerebellum does exist,” using the cerebellum to correct for nonspecific binding, appeared to be justified since the difference of cerebel- lar distribution volume between patients and NCs was 1 Association, All rights reserved.ry Cry fg 2. asiliga bigot aurora and paring tremaprir ina nora cnt (NG) abject anna patent with Paka disease (PD): Dopamine transporter Binding was mag 8 to 73 mute altar necton of ["C]WINES428, and th nage was normalized to animum of Oana mani ay conerraon of 150 nlm. pe ilcwa jected doze), Sertonin anspor binding vas aged 85 oS mn ter nection o Tcieis}682. andthe image was nail to's mnmum of nda maori att eonanratn of 100 GU pe male ejected doe) not significant. The cerebel K, was 14% lower in the mansis conllicting regarding this issue. wan in the NC group; if this effect results in a bias, not be stated unequivocally that previous ¢ adioligand bindiny im PD subjects would be cation use did not alter DAT or SERT bindiny than calculated, and it could falsely blunt but correlations between disease sa ingand not augment the difference between the roups. «that potential medication-related effects on The potential role of antiparkinsonian medi deserves comment. Althouigh subjects had not taken their ng were not robust. methodologic issue related to ions foratleast 12hoursatthe medication use is that at the time PD patients under "ET studies, their hronic use prior to these went clinical evaluation to assess the severity of their dis: studies could have potent SERT binding ly influenced DAT and/or ease, they were usin hharacteristis, Imp. antiparkinsonian medications, This ld potentially have confounded measures relating to studies do not support the view that these me lead to. severity of illness, However, despite the use of medica- nsin monoamine transporter binding or tions at the time of clinical assessment. affinity." The limited available data collected in hu gnificant cor ‘and ["C]) relations between striatal [!"C]WIN35 424 ‘Downloaded From: hitps:/fjamanetwork.com/ on 01/21/2022,7 fn s 2 20 gs ° g : : ° 5. . é ooo 205% cane 058 2075,PDOH) i Ey MoD Puamen ry % Figure 3. Colton betean binding of ("0 HeNSE82 and [Ch ain th puter Data represent the average bang of the "ight and lot sides. Open eras epresant normal age-matched contol (ncidh cored ele, pants win Pakineon dase PO) (n= 13). The ‘agression Ine rears tthe pooled dla. Onna ditto vole tape bang MeN5652 binding and disease stage were noted, suggesting that medication did not mask disease stag” ing Although data from the present study indicate that both dopaminergic and serotonergic systems are altered, in PD, the pattern of changes in the 2 systems differs. In particular, group differences in DAT binding were much [greater in the putamen than in the caudate nucleus, and the contralateral-ipsilateral ratio of DAT binding in the putamen (but not the caudate) was strongly related to asymmetry of clinical signs and symptoms. Conversely, ‘group differences in SERT binding were greater in the ‘caudate than in the putamen, and the contralateral- ipsilateral ratio of striatal SERT binding did not relate to asymmetry of clinical presentation. These findings sug- zgest that the disease process alfects DA and 5-HT net rons differently. Whether this is due to differences in the topography of the 2 systems or to some other factor re- mains to be determined. In conclusion, our findings indicate that the den- sity of striatal SERT, similar to that of DAT, is reduced, in PD, and that reductions in SERT correlate with dis- ‘ease stage. Additional studies are needed to identify the functional consequences of loss of serotonergic inner- vation in PD and to identily potential interactions be- toveen DA and 5-HT neurons in the context of the dis- ‘ease process. Accepted for publication May'9, 2003. ‘Author contributions: Study concept and design (Drs Ricaurte, MeCann, and Szabo); acquisition of data (Drs Kerenyi, Schretlen, McCann, Mathews, Ravert, Dan- nals, Hilton, Wong, and Szabo); analysis and interpreta- tion of data (Drs Kerenyi, Schretlen, MeCann, Varga, Hil- ton, and Szabo); drafting ofthe manuscript (Drs Kerenyl, Ricaurte, Schretlen, and Szabo); critical revision of the manuscript for important intellectual content (Drs Ricau- re, Schretlen, MeCann, Varga, Mathews, Ravert, Dan- nals, Hilton, Wong, and Szabo); statistical expertise (Drs Schretlen, Varga, and Hilton); obtained funding (Drs MeCann and Szabo); administrative, technical, and ma- (aepnnyreD) ARCH NETROUNOL a SEPT (©2003 American Medical Ass ‘Downloaded From: https:/jamanetwork.com/ on 01/21/2022 terial support (Drs Kerenyi, Mathews, Ravert, Dannals, Wong, and Szabo); study supervision (Drs MeCann and Szabo). This research was supported by US Public Health Ser- vice awards AG 14400 (Dr Szabo), DA 05938 (Dr Rica rte), DA 10217 (Dr Ricaurte), DA 09482 (Dr Wong), and NS38927 (Dr Wong) Corresponding author: Zsolt Szabo, MD, PhD, Depart ‘ment of Radiology, Johns Hopkins Medical Institutions, JHOC 3233, 601 N Caroline St, Baltimore, MD 21287 (¢-mail zszabot®jhmiedu). LES} 1. Joga te destopmens int pathology of Pans’. Aa rot to0s316 2 UNLGR WatherD Mash, Faucauc 8, avy F.Oopaine anspor ressenger An Paine’ ese nd col saben nga eros. ‘neuro 19843540456, 8 Gayl A Hisch€C Ag. ThigotialsytninPukison's dase ‘ay eral 0008:17-20. 4 Mil, riko JD, Pare, tl. manocheizl anaes over ‘mana vansprar (MAT) pron Patinso's se Bp Meal 10, ‘see 18 5 Bracks 0 Morphol an nctonal imaging tus on te dagrsi and proyassion of Parinsn's disease. J euro! 2000247 supl 2} 1. 6 Boo Tinh 6, Whegea Van Rayen EX. Imaging he depsnc- ‘e mucranamssn st ung gle halon smn trea and Fesivon emisonomogaphy in pabrs wih pakisonism. Fur Nl Med San026-71-182, 7 isan Cash R, Ag Y. Parison’ disease decreased dens of imipramine ar-prcacine Bing sein putamen Neva 185 S6555- 0, €.Halifay@¥,Bmbegs PC, Coton AGH lssng WM Gate LB. Lars stom srauen-ansubsncePenahingrearsin Patino’ disease. Bran Fes ogStO L107, 8. chiagi 6, Landvehmayer, Pot Palaces IM. Srtninargi tial ‘arepararsaredifearaly fecad i Fans’ dase an poyessive s- Franck ly am atordagrapi sud wth Hepa, Aevasiencs Sonese aco, loco RP Kujo SM, ANnan Zimerman Gl, Maeda, Pastin RD. Cansnatans online atta eesates nthe ea et ‘ospil uitatanced Parsons alos with sere postualinsabity 2 ates. Jer Transm 197 1451-89 Han agin PJones OW, ea Reduced etl eratanin anspor in labels AvP 1098 5515-1508, stom KA. Kuti JT, Aanen Vann [12 bt aaa fo erin pala sts preparation and pray SPECT su cor Me, 108436128131, Bruce, Kaho, Argbager Arian, asin Pda SPECT imaging a dopamine and eeratonn ansportrs wh [1128bes-CIT— ‘Noaing hes th uman ran Neral Tasso, 198 137-16. ‘ko 2, Schall, thon Ul Kei ale of "CNS ao- tein vnsprr olga Cer lod Flew Men. 198610967981, StU, sao 2 Mathews WE, Inv eectn of het an lg term MOM ners poston emsiontomayapy stu inh eg boon bain. Snape 1908 26189-12 cam UD, Sabo 2 Set! U, Onna F, Rau GA Psion emission Tamegraphiceece of toe act of MDMA est") on brain secon eats huran bigs. Lancet 008352 458 U7. Hogs Os, Kir L Lace Acura of ln agneitiio- pati Ponsa’ seas J Newel NewosurPayehzy. 80255-81184 Hamiton A ratig seal eprasion. J Mew Nasu Psych. 160; 2a Fis MB, pve RL Gabe , Was BH. Smuctre Cn Ie for ‘SUL Aus Disorders Washinton, 0: Arian Pye Pres, 106 Foleo MF Flsin SE. Metgh PR. Min marl state racial gue for (ying se eral state of pales forte cian, J PaycRs. 1875:12: ‘ei osha Mi, alr MD_Pakinsoni: onset progression rd arty Neves ogy Os i7aer-2, Fat, En andhe UPDRS Delp Comm 20 2 2 Unies Pakvan's lation, All rights reserved.a 2 28 a. Ey Ey o a 2 Downloaded From:: sas Rating Sl. IFS, Marsen CO, Cale 6, Glisten es. e- nt Develpnsin Parkinson Disease Fata Pat Wi: Marla Heath are tron, 187 15216, Ukfranocpie sexe Grup. ramos Piao’ ee aol bind stay comparing “wl and “haha” npeducary dosage fg tans in cd ova gatas J Neo euros Paci, 989527780 itor Yolo‘, Dnnals RF, Rave, Sete Z, Wong OF Colamn-sucing HPLC torte aaj of plea in FET nano tte, a iol 200 arses a Xavi GP. ata race or ent ata aces. EE Compa Grp op. 1000107642. Woods, Chery SR, Mazin Capi utonsted algorihen fo algingand reling PET ages. J Compu Assist Tomogr 108216820538 Fie J, Lig ogre Kuo Russie U, ine UK. PET ‘xairtonf he monoanine anspor witha anda CFT inet Parkinsons dese. Srapse 1005 2197-10. Frey MA Koope RA Kibour tl resp manganese in Paris's seus and normal aging, Ar Neo 106640873884, ga ann Mure. Musa Mana K Usman ‘othe egal aeblead parton escent of wr sing jar paszen ‘enssononoyapy. J oe lod Flow eta 1980327885, Sahl, Hue MF Dubey SD Sone comments on aque used mule endpoint astra mated ical al Stat Ma 1057 16:2520 2502, nei aan Ruse tal SbzalupatectaolPET igs e- CT tried nen Panes eee. Spee 1000.7:110 124 Frost. Rosier A, ich SO, ta Psion erssion toma apg ot ‘the copa nanan with "O]WD35 128 vals marke Secs ri Piso’ sense, Am Hawa 1553423 31, (wpm rep) XRCHNEROUVOL SEF Sa 2 28 2. ©. 4 uci ¥, Yost Okada, tl Auton ning te das of o- aie wanptr inte tiat, err cae. an yaa ney Paris's is compariert also p-F ing wh posronemi- sion tay Aan Mew 1085-01510. bso ae Lec ea Doarierge nein ar opin ans Pork bining assessed wth sion emission ography i Pakinsoa Gs Arch aura 20250580 $95, lr Fars Jun et (123et-TSPECT vuln dpsine "anspor loss in de nove parkinsonian tien. Eur Neurol 1098 SB rote Vane Mt Maer JM Rapa an velar eaiaton inhuman ian of Fparxetne bing, mare of secon up sis Bi Pech 108824200300. StU, Start, Kim SE hers MD, oa JW, Kuta AU. Ett dop- ner drugs othe vie indigo PWM 3528 a canal dpanine anspor Spee. 1906236188. Yeghajan SX, Andesn SL Baldessarini Ry Lack ttt terol line or slogiine on dopamine an stotoin anspor in at cause putamen or macs accumbens spt. euros Let 197296147150, Gata TaanL, Lana SZ et often nexne ih sdecivemno- amie oases and spec hyarxjypane pais on [shprnee ting ster oil manaraes of he a Mere macoly1057 26108-1082 GatmanM,Stevar O, Huse 0, Wison A, Hol, Kish Slee of L- Sop and ramp on staal opr anspor ex PD. Newly abs 15501564 Innis. Mare KL Skt, tl tet of stati -dopaeabiop oe [CStin on stil dopainewanparer SPECT imaging wth [et (i oy iors 100-1464. (©2003 American Medical Association, All ights reserved. https:/fjamanetwork.cony on 01/21/2022.