Regional striatal DOPA transport and decarboxylase activity in Parkinson’s disease. J Nucl Med

Regional Striatal DOPA Transport and Decarboxylase Activity in Parkinson's Disease Hiroto Kuwabara, Paul Cumming, Yoshifumi Yasuhara, Gabriel C. L@ger, Mark Guttman, Mirko Diksic, Alan C. Evans and Albert Gjedde McConnell Brain Imaging Center, Montread Canada; Montreal NeUrOlOgicalInctitute@Montrea4 Canada; and Depwiment ofNeumlo@jt and Neuroswge,y, McGill Unive,@ity Faculty ofMedichze Montrea4 Canada

@

the uptake constant correlates with the clinical stage of the Mthods: We measured blood-brainbarrier transport and de disease and aids differentiation from other movement dis carboxylatlonof 6-[1@I9fIUOrO-L-DOPA (FDOPA)usingPET in orders, including multiple system atrophy and progressive patientswith Parkinson'sdisease(n = 7, 57 ±7 yr) and age supranuclear palsy (7,9,10). Within the striatum of Parkin matchedcontrolsubjects(n = 7, 60 ±6 yr).To visuallypresent son's disease patients, the uptake constant is lower in regionalchangesof FDOPAuptakein Parldnson'sdisease,we putamen, especially in the posterior part than in the head of introducedmapsof FDOPAuptakereIa@ve to o@pItaIcortex@ the caudate nucleus (7,11). averagedacrosscontrolsubjectsand Parkinson'sdiseasepa The uptake constant of FDOPA, however, represents tientsin an MRI-baSedstereotadccoordinatespace.Results: TherewasnosignIficantchangesinthe blood-to-brain transport the combined effects of the two key steps of FDOPA ki of FDOPA (K@)in Patldnson's disease. The K@values of the netics; the transport of FDOPA across the blood-brain head of caudatewere lowerthan those of putamenIn both barrier (BBB) and decarboxylation of FDOPA by L-dopa normal subjects and Parkinson's disease patients. In Parkin decarboxylase (E.C. 4.1.1.26)(DDC) (9,12). Separate mea son'sdisease,theactivityof L-DOPAdecarboxylase (DDC)was surements of these steps are important in Parkinson's dis d@Ierenbally reducedin subdM@onsof stñatum. The resklual ease for several reasons. First, pathological changes of the DDCactMtywas63%ofthecontrolvalueintheheadofcaudate blood-to-brain transport in Parkinson's disease are not well nucleus,54%in the anteriorputamenand39%in the posterior documented, although the delivezyofexogenouslevodopa, putamen.The DDC @ivity. in frontaland occipitalcorticesre @ned unchangedby the disease.Subtrar@tion of averaged the majortherapy for the disease, entirely depends on this FDOPAuptake maps (controlminus Parkinson's disease) visu facilitated transport. Recently, Alexander et al. reported @.ed a spa@al patternof pathologioalchangesin FDOPAup significant reduction of the blood-to-brain transport of takecommonto Parkinson'sdiseasepatients.Conclusion:The levodopa in MPTP parkinsonian monkeys (13). Second, striatalbIood-to-br@ntransport of FDOPAremained unchanged despite discontinuation of therapeutic levodopa prior to whilethe DDCactivitywas diI!erentiallyreducedwI@nthe stri PET studies, the major plasma metabolite, O-methyl-L atum in Parkinson'sdisease.We found the FDOPAu@ake dopa, may persist in plasma due to a longer plasma half mapsusefulin identifyingalteredpatternsof FDOPAmetabo life, and interfere with FDOPA transport (14). lism common in Parkinson's disease. In the present StUdy,we present estimates of the blood Key Words: Parkinson's disease; striatum;L-dopadecarboxyl to-brain transfer (Kr) and the relative activity of DDC (kr) ase;biood4@br@n transportfun@oni maps in patients suffering from Parkinson's disease. To empha size a pattern of regional neurochemical pathology of the J Nuci Med 1995; 36:1226-1231 striatum in Parkinson's disease, we grossly subdivided the striatum into the head of caudate nucleus, and the anterior and posterior portions of putamen.

@ I has been demonstrated that 6-['8Fjfluoro-L-DOPA Visualization

and recognition

of the spatial pattern of

(FDOPA) and PET are useful in monitoring presynaptic FDOPA uptake by means of pixel-by-pixel images is in dopaminergic neurotransmission in the human brain (1—3). tended to facilitate clinical diagnosis. Parametricimages of FDOPA-PET studies are commonly analyzed by graphical K? and k@are not currently available due to the statistical analyses for estimates of the net clearance rate constant of noise of measurements made with PET. For this reason, ratio― FDOPA into the brain, often collectively referredto as the we extend the concept of so-called “striato-occipital ratio―images to extract combined ef uptake constant of FDOPA (4-8). In Parkinson's disease, to “pixel-occipital fects of Parkinson's disease on the blood-to-brain transport and DDC activity. Analogous to the techniques used in the Received May101994; revIsion a@ceç@ed Nov.29,1994. functional mapping of the brain, images are transformed to For correspondence or repdn@om@

Hlr@o Kuw@wa, MD, PhD, PET

Cetler, RobertC. ByrdMaui ScienceCenter,WestWglniaUniversity,P.O.Box 9183,Morgwihown, WV26506—9183.

1226

an MRI-based

stereotaxic

coordinate

space,

averaged

across control subjects and Parkinson's disease patients

TheJournalof NuclearMedx@ine • Vol.36 • No.7 • July 1995

and subtracted to elucidate changes common to Parkin son's disease (15,16). MATERIALS AND METhODS

subdividedinto anteriorand posteriorhalves.The occipitalROIs were used to construct pixel-to-occipital radioactivity ratio im ages. We identified the three striatal structures in at least four

consecutivematchedMRIplanesand used the middletwo planes foranalysis.Thetimecoursesof radioactivityin thesestructures

Patients and Subjects were obtainedby applyingthe stored ROl templatesto successive WestudiedsevenpatientswithParkinson'sdisease(age:57 ± PETframes,andweightedaveragesfortheabovestructureswere 7yr)andsevenhealthy,neurologicallynormalvolunteers(60±6 obtained. We treated the left and right sides of striatal subdivi

yr). All subjects gave written,

informed consent to the study,

previously approved by the Ethics and Research Review Corn miftee of the Montreal Neurological Institute. The normal sub jects were recruited from the general public and screened for past and present medical and psychiatric histories, including substance

abuse. The patientswere seen by a neurologist(MG).The patients

sions separately on the grounds that Parkinson's disease may

haveasymmetricpathology.For the corticalregions,the radio activity time courses were weighted averaged for the two sides.

DataAnalysIs Inthefrontalcortex,we estimatedtheunidirectional blood-to

sufferedlocomotordisabilityon Stages 3—4 of the Hoehnand brain clearance (K?), the partition volume (V@ = K1/k2, where k2 Yahr scale onset within 3—5 yr at the time of PET study (17). is the fractional brain-to-blood clearance), the relative DDC ac Patientswere treated with 400—1100 mg levodopaper day. Three tivity(ky) and the effectivevascularvolume(Va),usingradioac patients received bromocriptineand one deprenyl in addition to tivitytimecoursesinbrainand plasmarecordedduringthe first60 levodopa,whilethe remainingthreepatientsrecievedlevodopa mm followingtracerinjection.We constrainedthe ratioof the carbidopaalone. All medicationswere interruptedat least 12hr unidirectionalblood-to-brainclearancesof FDOPA and OMFD to prior to the PET study. All subjects were fasted overnight and 2.3 (21). In the striatal subdivisions,we estimated only K@,k@ pretreatedwith100rngcarbidopaapproximately 90mmbeforethe and V@,using data obtained duringthe first 40 mm of the study. PETstudy. Weconstrainedthepartitionvolumetotheestimatesof thefrontal cortex of individualsubjects. The use of these biologicalcon PET Procedures Subjects reclined on a couch and head movement was lightly

straints has been validated (22,23).

and discussed

in detail elsewhere

restrainedwith a custom-madehead holderof rapidlysetting foam. Thin catheters (20-gCathionIV) were placedin a brachial Averaged Images arteiy for blood samplingand an antecubitalvein for tracer injec We normalizedthe radioactivityof each pixel to the average tion. The study room was dimly lit, quiet and maintained at occipitalradioactivitybetween60 and90 mm.The ratioimages 20-23°C. were transformedto a commonstereotaxiccoordinatespace During90 mm after intravenousadministrationof 200 MBq of basedon the atlasofTalairachand Tournoux(24)but re-scaledso FDOPA, we recorded the radioactivity in the brain with the Scan

ditronix PC2048 15B (Upsala, Sweden) PET camera. The PET

that the lengthof the transverseand sagittalaxes were equal (15). These transformedimages were averaged across subjects of the

camera has an in-plane resolution of 5.8—6.4mm and an axial

sameclinicalcategory(i.e., controlsubjectsandParkinson'sdis

resolution of 6.1—7.1 mm FWFIMwith 15 simultaneousplanes (18). The frame schedule was six 30-sec frames followed by seven

ease patients) (16). The averaged patient and control images were

subtracted(controlminusParkinson'sdisease), andnormalizedto

1-rain,five 2-mm, four 5-rain and five 10-mmframes. Arterial thecontrolimage,toyieldchangedistribution images.Theabove blood samples were taken eveiy 10 sec in the beginning and at

functionalimages could be merged with the averaged MR image

increasingintervalstoward the end of the study. Followingcon with color display.We presentedimagesin a gray scale with trifugation,radioactivityin arterialplasmawas determinedwith superimposed grids to aid MR-PET correlation. All images were the Canberra802-3W well-type scintillation spectrometer (Ram

taken from the transverse section of the brain parallelto and 3.7

sey, NJ) cross-calibratedwith the PET camera and correctedfor

nun above the AC-PC plane, the transverse plane passing through

the plasmavolume. Plasmasamples taken at 2.5, 5, 10, 15, 20, 25, the anteriorand posterior commissures. 30, 35, 45 and 60 mm were fractionated by high-performance

liquidchromatography (HPLC)with one-linegammadetection Statistical Methods

Results were expressed as means and standarddeviations. We (Berthold LB 507A) to separate radioactive species in plasma (19). We found FDOPA and 3-O-methyl-6-[18F]fluorodopa used Student's t-tests to compare means and paired t-tests to

(OMFD)to be the majorplasmaradioactivitysources.Minor plasma metabolites, includingsulfo-conjugatesof 6-['8F]fluoro dopamine(< 5%),were assumednotto enterthe brain.Priorto theFDOPAstudy,tissueattenuationwas determinedwitha 511keVgammasource(@Ga).EachPETframewasreconstructedto a 128 x 128matrixof 2 x 2 mmpixels (25.6mm@in volume),

comparethe same variablein differentstructures (includingsub divisions)withinthesameclinicalcategories(Parkinson'sdisease patientsor controlsubjects).The nullhypothesis(equalmeans) was rejectedat or less thanthe 0.05 level. The p valueswere corrected for multiplecomparisonsaccordingto the Bonferroni procedure(25).

correcting for tissue attenuation, deadtime, scatter and coincident

counts. On a separate occasion, we obtained 64 2-mm thick axial T2-

weighted MR images. The MRI volume was co-registeredwith a

three-dimensionalPET transmissionvolumeand MRimageswere re-sampled to the plane of PET images (20). We identified and

RESULTS

The areas of striatal subdivisions identified on matched MR images were 1.44 ±0.23 cm2 for the caudate head, 1.82 ±0.30 @2for

@2 for the anterior putamen and 1.56 ±0.31

putamen in control subjects, and outlinedthefrontalandoccipitalcortices,headofcaudatenucleus @2, 1.78 ±0.39 cm2 and L55 ±0.33 cm2, andputamenon matchedMRimages,thusobtainingthe individ 1.52 ±0.27 ual's template of regions of interest (ROIs). The putamen was respectively, in Parkinson'sdisease patients. Therewas no

DOPADecarboxylasein Parkinson's Disease • Kuwabaraet al.

the

posterior

I 227

TABLE I Un@irectionalBlood-to-BrainClearanceof FDOPA (Kr)

0.15

,

,

,

,

,

0

subjects min1)Frontal RegionControl @

@

@

disease 0.10•

(mlg1 mln1)Parkinson's (mlg1

0.007Occi@ cortex0.031 0.010Caudata cortex0.039 0.008Anterior head0.032 0.011*Posterior putamen0.042 0.01?*p putamen0.046

±0.0050.029

±

±0.0100.037 ±0.0080.033 ±0.0090.040 ±0.008k0.041

± ± ± ±

7 a

0

I

9

0.05

@. •

Parkinson's disease patients. We found no statistical dif ference between patients and controls. Table 1 lists regional values of the unidirectional blood to-brain clearance of FDOPA. In frontal and occipital cor tices and striatal subdivisions, we found the K? estimates of Parkinson's disease patients were not statisticallydiffer ent from those of control subjects. The anterior and pos terior putamen K? values were significantly greater than those of the caudate head in both control subjects and Parkinson's disease patients. Table 2 lists regional values ofthe relative DDC activity. We found no significant changes in the k@estimates be tween control subjects and Parkinson's disease patients in both frontal and occipital cortices. Among striatal subdivi sions ofcontrol subjects, the k@values were highest in the anterior putamen and lowest in the caudate head. We found no statistical differences among the k@values of different striatal subdivisions in control subjects. In Par kinson's disease patients, the DDC activity was most pre served in the caudate head, and most severely impaired in the posterior putamen. The residual DDC activities in Par kinson's disease patients were 63% in the caudate head,

TABLE 2

0

•

NCPD Caudate

I

I

I

I

I

NCPD Anterior

NCPD Poeterior

Putamen

Putamen

L-DOPAdecarboxylase(kg)forthe caudate nucleushead and the anteriorandposteriorsubdMsions ofputamen.Opencirclesarethe k3Dvaiues of normal subjects; dosed circles are Parkinson's disease

patients. 54% in the anterior putamen and 39% in the posterior

putamen ofcorresponding control values. The k@values of the posterior putamen were significantly lower than those of the caudate head and anterior putamen in Parkinson's disease patients. Figure 1 plots individual k@values in striatal subdivi sions for which means and standarddeviations were listed in Table 2. In the caudate head, 6 of 14 parkinsonian k@ values were lower than the lowest control k@value (the left and right sides of striatal subdivisions were treated inde

pendently). In the anterior putamen, all but one of 14 parkinsonian values were lower than the lowest control value. In the posterior putamen, there was no overlap between

parkinsonian

and control

values.

There was no

distinctive gap, however, between k@ values of Parkin

son's disease and control subjects in any striatal subdivi sions. Figure 2 shows the normalized averaged pixel radioac tivity images for control subjects (Fig. 2A) and for Parkin son's disease patients (Fig. 2B), the relative change image (Fig. 2C) and the averaged MR image (Fig. 2D) for a trans verse section parallel to and 3.7 mm above the AC-PC plane. For control subjects (Fig. 2A), the radioactivity was in the striatum, and the ratio was

relatively uniformthroughoutthe cortex with a slight fron tal-to-occipital gradient. For Parkinson's disease patients

ControlParldnson'ssubjectsdiseaseReg@n

(min@')(@-1) 0.006Occipital Frontalcortex0.010

±0.0020.009

±

0.006Caudate cortex0.009

±0.0010.007

±

0.015*Anterior head0.076 putamen0.080 1@Posterior putamen0.071

±0.0220.048

±

±0.0130.043

±0.01 ±O.OiO@

±0.0120.028

!

FiGURE 1. Plotsof indMduaivaluesof the relath,eacbvityof

specifically accumulated

RelatIveDDCActivity(k@)

0

:

Head

control subjects and 0.66 ±0.12 and 0.68 ±0.13 ml g' for

§• 0

S

< 0.05;caudateheadvs. anterioror posteriorputamen.

significant difference between areas of these striatal subdi visions of patients and controls. The partitionvolume (Vt,= K1/k,) averaged 0.69 ±0.10 and 0.66 ±0.12 ml g ‘ in frontal and occipital cortices for

0

0 8.

0,.@ -1@

0 0

(Fig. 2B), striatal accumulation of activity was limited to the caudate head and, to a lesser degree, to the anterior putamen. The relative change image (Fig. 2C: Fig. 2A minus Fig. 2B, normalized to Fig. 2A) confirmed that the pathological change was most evident in the posterior pu

tamen of Parkinson's disease patients. DISCUSSION

*p < 0.0005;tp < 0.0001; oontrol sub@ vs.Parldnson's disease

We demonstrated a differentialreduction of the relative DDC activity in subdivisions ofthe striatum in Parkinson's

1228

TheJournalof NuclearMedicsne • Vol.36 • No.7 • July 1995

A

2-SB

2

ZI

II1@@!:4: •ttL

@ C

FDOPA study including the k@ coefficient used in the present study and by Huang et al. (27), the slopes of graphical analyses normalized to plasma FDOPA activity

(6) orto theradioactivity of a reference region(7,8),and

I.

‘4

07

07

Os 0

.4

03

t2

the simple striato-to-occipitalactivity ratio (28). We found the present method one of the most powerful in discrimi nating between normal and pathological FDOPA kinetics in stiiatum ofpatients with Parkinson's disease (12). In the

present study, we observed no overlap in the k@values of the posterior putamen of control subjects and Parkinson's disease patients. In the anterior putamen only one k@value of a Parkinson's disease patient fell within the normal range. Brooks et al. and Sawle et al. also reported similarly good discrimination between the two groups in putamen by means of the uptake constant (7,11). Biochemical

studies of postmortem

brain revealed

a

large variation of the normal striatal DDC activity both

FiGURE 2. The pixelvalue-to-mean ocdpftalradioactMtyratio among reports and within individual reports (the coeffi

images of indMdualsut@ectsare firsttransformedintoa common streotaxicspaceof theatlasof TalairachandToumoux(24) and resealedso thatthelengthof thetransverse andsagittalaxesare equalto eachother(15). (A)TheaveragedpixelradioactMty im agesforcontrolsubjectsandParkinson's diseasepatients(B).(C) TherelativechangeImagewascalculatedas in Agure2A minus

cients of variation of 30%—60%) (29—32), probably due to the variable duration between death and examination, af fecting the stability ofthe enzyme (30). The changes of the striatal DDC activity in Parkinson's

disease also vary sig

nificantly among reports from 4.4% (29) to 44.5% (31) of Figure 2B, nOrmaliZedto Figure 2k (D) The averaged MR image at the control value for putamen. Agid et al. (33) reported 3.7 mmabove the AC-PCpisne,the levelof the averagedPET reductions of DDC activity to 45% of the control value in images. caudate nucleus and to 25% in putamen as the mean of the literature values. Thus, the present method yielded values

for the reduction in relative DDC activity comparable to values in vitro. The magnitude of reductions observed anterior gradient was reported previously by Leenders et postmortem are slightly greater than the present observa al. (9) using the influx constant ofFDOPA which “includes tions in vivo, perhapsdue to differentstages ofthe disease. effective blood-to-brain transport and specific processing Quantitatively, observations made with FDOPA and of the tracer by the tissue.―The following points are PET indicate a reduction of the k@or the uptake constants unique to the present study. First, the present FDOPA to 40% of the normal values in patients with moderately PET method yielded direct measurements of both the rel severe Parkinson's disease. In contrast, postmortem as ative DDC activity and the unidirectional blood-to-brain says indicate a strikingly severe reduction of striatal dopa clearance. Second, we improved the anatomical identifica mine content to around 10% of the normal value (34). This tion of the cortical regions and striatal subdivisions by severe depletion of dopamine relative to a modest reduc mapping of correlated MRIIPET volumetric data onto a tion ofthe DDC activity remainsto be studied in the future. standarized stereotaxic coordinate space. As possible explanations for the discrepancy, we have The constraints ofthe present method were derivedfrom proposed a competition between decaboxylation and efflux the theoretical and practicalobservation that the two steps of L-DOPA to the circulation (16). We also demonstrated of tracer FDOPA metabolism in brain, namely the trans increased dopamine turnover and reduced retention of do port across the BBB (26), and the enzymatic conversion to pamine in Parkinson's disease (35). fluorodopamine, are both governed by Michaelis-Menten We found no significant change of the unidirectional kinetics (22). First, we constrained the transport ratio be blood-to-brain clearance of FDOPA in Parkinson's dis tween OMFD and FDOPA, the main metabolite of periph ease. In MPTP-treated monkeys, the results are controver eral origin and competitor for the large neutral amino acid sal. Alexander et al. (13), using a microdialysis technique, transport, to 2.3 (21). Second, we constrained the tracer reporteda significantreduction ofthe blood-to-braintrans partition volume of striatal subdivisions to the individual's port of levodopa, while data from Doudet et al. (36) sug estimate ofthe frontal cortex (23). The constraints had two gested no change of the transport of OMFD. Our findings advantages; circulation time for data analysis could be may be further confirmed by using tracers specific to the disease in vivo with the posterior half of putamen being most severely affected. A similar subregional posterior-to

limited to 40 mm during which the loss of fluorodopamine

metabolites from brain is likely to be negligible, and they yielded accurate estimates in smallerstructuressuch as the caudate head and subdivisions of the putamen. In a previ ously publishedarticle, we comparedanalyticalmethods of

DOPADecarboxylasein Parkinson's Disease • Kuwabaraet al.

large neutral amino acids such as OMFD and [“C]-ami

nocyclohexancarboxylate (37,38). According to Crone's equation, the K1 coefficient is a function of cerebral blood

flow and of the permeability-surface area product (39). Leenders et al. (9) reported no significant change of cere 1229

bralblood flow in the caudate and putainenof Parkinson's disease patients. This finding along with our own results

ResearchCouncilof Canada. Carbidopawas kindly suppliedby Merck Frost Canada, Inc.

suggest no pathological changes in density and function of

large neutral amino acid transportin Parkinson's disease. The rate of dopamine synthesis from exogenous, therapeu tic levodopa can be calculated as CaKD, where Ca 15the concentration of levodopa in plasma and K'@the net clear ance of FDOPA, analogous to measurements of cerebral glucose utilization. KD is given b@rK@k@/[k@ + k@J,where k@is the fractional brain-blood clearance. Therefore, im parment ofBBB transport, were it present, would diminish levodopa deliveiy to striatum and also subsequent dopa mine production. Interestingly, the caudate K@values ofthe present study were 70%—@82% of putamen values. Koeppe et al. (38) reported that the caudate K1 values of [“C]-aminocyclo

hexancarboxylate were 72% of the putamen values in nor mal subjects. In addition,Leenders et al. (9) found regional blood flow values of caudate were 83%—'84% of the puta men values in both normal subjects and Parkinson's dis ease patients. This quantitative agreement supports a suc cessful separation of blood-to-brain transport and DDC activity in the present method. The striatal-to-occipitalradioactivity ratio is an index of FDOPA uptake by the striatum (28). The ratio significantly correlated with the DDC activity for normal subjects and for Parkinson's disease patients (12). Maps of this index ([pixel-occipitalj/oceipital) have been used to detect post operative changes in FDOPA uptake in Parkinson's dis ease patients who received transplantation of fetal dopa mine neurons (40). We transformed such ratio images to a common stereotaxic coordinate space and averaged across subjects of the same clinical categozy to present a pattern ofFDOPA accumulationcommon to the disease (16). Such averaged images can provide a characteristic pattern of biologicalvariables associated with diseases. In this study, we also provided a map of changes in FDOPA uptake and metabolism

common

to the present

patient

group.

Thus,

we propose that FDOPA, in analogy to cerebral activation studies, can be used as a clinical tool for identifying an abnormality of biological variables in clinical groups as compared to normal subjects.

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miogicClinics1992;10:421—433.

3. CaIneDB,SnowBJ.PETünaging in Parkinsonism. AdvNeurol1993;6@ 484-487. 4. Patlakcs, Blasbcrg RG,FenstermacherJD. Graphical evaluation ofblood to-braintransfer oonstantsfrom multiple-timeuptake data. I Ceith Blood F1OWMetOb 19833:1-7. 5. Patlak cs, ai@t,e@ RG. Graphical evaluation of blood-to-brain transfer

constants from multiple-timeuptake data: generalization.I Cei@bBlood FlowMetab 19855:584-590. 6. MartinWPW,PalmerMR, Patlak @S, CaineDB.NigrOstiriatal function in humans studiedwith positron emissiontomography.Ann Neural 198926: 535-542.

7. Brooks DJ,Ibanez V, SawleGV,Ctal.Differing panerns ofstriatal ‘IF clopauptake in Parkinson'sdisease, multiplesystematrophy, and progres sive supranuclearpalsyAnn Newvl 1990;28:547-555.

8. Hartvig P,AgrenH, Reibring L, Tedroff J,Bjurling P,Kihlberg T. Brain kineticsofL-[@-―qDOPAin humansstudiedby positronemissiontomog raphy.JNeUra1 Tmnsm 1991;86:25-41. 9. Leenders ICL,SalmonEP,TyrrdllP. Ctal.Thenigrostriatal dopaminer@c systemassessed invivoby positron emission tomography inhealthyvol. unteer subjects and patients with Parkinson's disease.Awh Neurol 1990; 47:1290—1298.

10. SnowBi, Peppard RF, GunmanM, Ctal. Positron emission tomographic manningdemonstratesa presynapticdopaminergiclesionin Lytico-BOdig. The amyotrophic lateral sclercsis-parkinsonism-dementia complex of

Guam.A,t* Neuml 1990;47:870—874. 11. SawleGV,PlayfordED, BurnDi, OmninglianiVJ,BmoksDi. Separating Parkinson's disease from normality.Discriminantfunctionanalysisof flu oredopaF-18positronemissiontomogrphydat@AwhNeurol 1994;51:237243. 12. Hoshi H, KuwabaraH, Léger 0, CunimingP, GuttmanM, GjeddeA. 6-['8Fjfluoro-L.DOPAmetabolismin livinghumanbrain: a comparisonof six analyticalmethods.I CerebBloodFlowMetab 1993;13:57-69. 13. AlexanderGM, SchwartzmanRi, GrothusenJR, GordonSW. Effectof plasmalevelsoflargeneutral

amino acidsanddegreeofparkinsonismon

the

blood-to-braintransportoflevodopa in naiveand MFfl' parkinsonianmon. keys. Newvlogy 1994;44:1491—1499. 14. GuftmanM,LegerG,Cedarbaum 3M,Ctal.3-0-methyldopaadministration does not alter fluorodopatransportintothe brain.Ann Newol 1992;31:638643. 15. Evans AC, Marreft 5, Neelin P, et aL Anatomical mapping of functional

activationin stercotaxiccoordinatespace. Neum-Image 19921:43-63. 16. GjCddC A, lAger 0, QimmingP. et al. StriatalL-dopadecarboxylase activity in Parkinson's disease in vivo: implicationsfor the regulationof dopaminesynthesis.JNewvxhem 1993;61:1538-1541. 17. HoehnMM, YahrMD. Parkinsonism: onset, progressionand mortality. Neurology 1967;17:427—442.

cONCLUSION

The relative DDC activity was differentiallyreduced in subdivisions of the striatum in Parkinson's disease while the blood-to-brain transport of large neutral amino acids remained unchanged. PET imaging was useful in demon strating changes of FDOPA accumulation in Parkinson's

disease.

18. Evans AC, ThompsonCJ, Marret 5, Ctal. Performancecharacteristicsof the PC-2048:a new 15-sliceencoded-ciystalPETscannerforneurological studies.IEEE TransNucl Sd 199135:730. 19. OimmingP,L4gerG,KuwabaraH, GjeddeA.Pharmacokinetics of plasma 6-('8FJfluoro-L-3,4-dihydroxyphenylalanine ([‘FJFDOPA) in humans. I Cereb Blood Flow Metab 1993;13:668-675. 20. EvansAC, Marreft 5, TorrescorzoJ, Ku 5, Coffins L MRI-PETcorrelative analysis using a volume of interest (VO!) adas.ICe@b Blood FlOWMetab

1991;11:A69-A78. 21. ReithJ, GjeddeA, KuwabaraH, Ctal. Blood-braintransferandmetabolism of 6-['8F]fluoro-L-DOPA in rat. I Cereb Blood Flow Metal, 1990;10:707—

ACKNOWLEDGMENTS

The authorsthankthe technicalstaffof the PositronImaging Laboratories,includingthe MedicalCyclotronand Radiochemis tiy, for productionofthe radioisotopeand supportof the positron emission tomograph and Dr. Routens for valuable advice. This

workwas supportedby grantsP0-41 andSP-30of the Medical 1230

719. 22. GjeddeA,ReithJ,DyveS,etal.Dopadecathoxylaseactivityoftheliving

humanbrain. P@vcNaIACO4 Sd USA 1991;88:2721-2725. 23. Kuwabara H, Qimming P, Reith J, Ct al. Human striatal L-DOPA decar boxylase activity in vivo using 6-['@F]fluoro-DOPA and positron emission tomography: error analysis and application to normal subjects. I Cei@b Blood Flow Metal, 1993;13:43—56. 24. Talairach J, Tournoux P. Co.pla,marstereouodc atlas ofthe hwnan bmin.

TheJournalof NudearMedians• Vol.36 • No.7 • July 1995

Thft-dimeMionalpm@onal

systeni. an qyruach

to cei@bml imagü@g

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