Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:12-17

The nigrostriatal dopaminergic pathway inWilson's disease studied with positron emissiontomography

Barry J Snow, Mohit Bhatt, W R Wayne Martin, David Li, Donald B Calne

AbstractMovement disorders, including Parkin-sonism, are prominent features ofneurological Wilson's disease (WD). Thissuggests there may be dysfunction of thenigrostriatal dopaminergic pathway. Toexplore this possibility, five patientswere studied using positron emissiontomography (PET) with '8F-6-flu-orodopa (6FD), and magnetic resonanceimaging (MRI). We calculated striatal6FD uptake rate constants by a graphicalmethod and compared the results withthose of 18 normal subjects. It was foundthat four patients with symptoms all hadabnormally low 6FD uptake, and the oneasymptomatic patient had normal up-take. PET evidence for nigrostriataldopaminergic dysfunction was presenteven after many years of penicillaminetreatment. It is concluded that thenigrostriatal dopaminergic pathway isinvolved in neurological WD.

pathway in vivo." Following administration,radioactive metabolites of 6FD accumulate inthe striatal endings of nigrostriatal dopamin-ergic neurons. PET can image this accumula-tion and thereby display the anatomicaldistribution of the intact nerve endings.'2 Inaddition, tracer-uptake data gathered duringthe scan, can be used to derive a 6FD uptakerate constant. This constant is an index of theactivity of the enzyme dopa-decarboxylasethat metabolises dopa to dopamine."1Necropsy studies show that dopa-decarboxy-lase activity decreases with age and is dimini-shed in Parkinson's disease.3 '" PET studiesagree with this necropsy data, showingdecreases in 6FD accumulation with age andin Parkinson's disease." "'' In addition, PETis sufficiently sensitive to demonstrate asymp-tomatic dopaminergic lesions in humans andmonkeys.'8WD has not previously been studied with

6FD PET. We employed this technique todetermine if the nigrostriatal dopaminergicpathway is damaged in WD. We comparedfive patients with 18 controls.

Belzberg Laboratoryof ClinicalNeuroscience, DivisionofNeurology,Department ofRadiology, Universityof British Columbia,and the UBC/TRIUMF PETProgram, Vancouver,British Columbia,CanadaB J SnowM BhattW R W MartinD LiD B CalneCorrespondence to:B J Snow, Department ofMedicine, UniversityHospital, 2211 WesbrookMall, Vancouver, BC V6T1W5, CanadaReceived 21 December 1989and in revised form23 April 1990.Accepted I June 1990

Wilson's disease (WD) is an autosomal reces-sive disorder characterised by widespreadcopper deposition throughout the body, par-ticularly in the liver and brain.' Neurologicalpresentation varies with combinations of psy-chiatric disturbance, involuntary movements,incoordination and dysarthria; pyramidal tractabnormalities are minimal, and sensation isspared. Pathological studies,23 computerisedtomography (CT)45 and magnetic resonanceimaging (MRI) show that the predominantlesions are in the basal ganglia, particularlythe lentiform nucleus.The prominence of movement disorders,

including Parkinsonism, raises the questionwhether there is also a predilection for thenigrostriatal dopaminergic pathway to beinvolved in WD. There is only limitednecropsy information suggesting that thepathway may be damaged in WD.9 '° Althoughthe structural integrity of the striatum andsubstantia nigra may be studied with CT andMRI, these modalities cannot study the func-tional integrity of the dopaminergic system.Until now, there has been no satisfactorymethod of studying the function of the nigro-striatal dopaminergic pathway in livingsubjects.With the advent of positron emission

tomography (PET) using the tracer "F-6-fluorodopa (6FD), we can investigate thefunction of the nigrostriatal dopaminergic

PatientsThe diagnosis of WD was based on the fol-lowing established criteria in all patients:medical history, physical examination,Kayser-Fleischer rings confirmed on slit-lamp examination, low serum ceruloplasminlevels and elevated urinary copper excretion(table 1).2o The relevant clinical features of thepatients are presented below. No patient hadsymptomatic liver disease or had othersignificant medical illness. Standard* liverfunction tests were normal in all patients atthe time of scanning (alkaline phosphatase,aspartate aminotransferase, gamma-glutamyltransferase and bilirubin). None had a historyof exposure to phenothiazines or otherdopamine receptor antagonists. Whenstudied, no patient had ataxia, pyramidal tractsigns, or sensory changes. The control groupconsisted of 18 subjects (mean age 40-2 years,range 22-54); all were neurologically normaland none were taking medication at the timeof scanning.

Patient 1 was a 23 year old man who wasdiagnosed as having WD at age 12 whenhe developed predominantly Parkinsonianfeatures with slurred speech, clumsy handmovements, micrographia, and a slowed gait.There was an intention tremor of the righthand. He was started on penicillamine 2 gmdaily and improved steadily. When studied

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The nigrostriatal dopaminergic pathway in Wilson's disease studied with positron emission tomography

Table I Biochemicalfindings

Ceruloplasmin Urinary CopperPatient (mg/100 ml) (ug/24 hours)

1 <7 9302 <7 114*3 8 145*4 12 290*5 < 7 210*

*Measurement taken while on treatment.

the only abnormal findings were milddysarthria and impaired rapid alternatingmovements of the hands.

Patient 2 was a 28 year old woman whopresented at age 13 with tremor of the hands,drooling and slurred speech. Her twin brotherhad been diagnosed as having WD two yearspreviously. She took penicillamine for twoyears then stopped for unknown reasons. Atage 18 she was admitted to a psychiatric wardwith disinhibited behaviour, drooling anddystonic hand movements; she improved on

penicillamine. At age 26 she stopped herpenicillamine again and within a monthdeveloped inappropriate laughter, unintelli-gible speech and dystonic hand movements.On penicillamine 2 gm per day she improved.When studied she had mild dementia anddisinhibition, dysarthric but intelligiblespeech, and dystonic posturing of the upperlimbs. There was no tremor, and no Parkin-sonian features.

Patient 3 was a 37 year old man who was

diagnosed as having WD at age 30 when hesought an ophthalmological opinion regardingwhat were diagnosed as Kayser-Fleischerrings. Neurological examination revealed onlya mild intention tremor of the right hand. Onpenicillamine 1 gm per day the rings andtremor resolved. When studied he was

neurologically normal.Patient 4 was a 50 year old man who was

diagnosed as having WD at age 18 when hedeveloped slurring of speech, slow movementsand drooling. An older brother had died ofWVD. Treatment with 2-3-dimercapto-pranol(BAL) resulted in a modest initial improve-ment, but he subsequently deteriorated. Byage 30 he was bedbound with unintelligiblespeech, rigidity and weight loss. On penicil-lamine 2 gm per day he improved consider-ably. When studied he had predominantlyParkinsonian features with normal mentation,masked facies, dysarthric but intelligiblespeech, rigidity of all limbs, clumsy rapidalternating movements, an intention tremorand a shuffling unsteady gait.

Patient S was a 51 year old woman who was

diagnosed as having WD at age 27 when shepresented with slurred speech, clumsy handsand tremor of the arms. On penicillamine1 gm per day her symptoms stabilised. Whenstudied she had predominantly Parkinsonianfeatures with mild dementia, dysarthric butintelligible speech, a resting tremor of theright hand, rigidity, clumsy rapid alternatingmovements and an unstable gait.

MethodsThe methods employed for PET have beendescribed in detail elsewhere." The UBC/TRIUMF PETT VI system was operated inthe high resolution mode.2' The system simul-taneously collects data from seven contiguousaxial slices with a centre to centre separationof 14-4 mm, in-plane resolution averaging9-2 mm full width half maximum (FWHM),and an average axial resolution of 11 mmFWHM. A transmission scan, using a ringsource containing 'Ge, was performed beforethe emission scans to permit a measured atten-uation correction to be applied to the emissiondata.The patient's medications were withheld

from the night before scanning. All subjectsreceived 100 mg of carbidopa one hour beforethe scan. 6FD (2-0-3-5 mCi) was prepared asdescribed previously22 23 and administeredintravenously at the start of scanning. Duringthe scanning period 29 sequential blood sam-ples were drawn from an indwelling radialartery catheter, and the total radioactivity ineach was determined in a well counter. Twelvesequential emission scans were performed,each of 10 minutes duration.A graphical method was employed to cal-

culate the steady state 6FD uptake rate con-stant for the whole striatum." 24 25 This methodincorporates both the measured blood radioac-tivity and the corrected striatal radioactivity.To determine striatal radioactivity, ellipticalregions of interest (ROI) were applied visuallyon all slices in which radioactivity in excess ofbackground was evident. To ensure inclusionof the whole striatum, a 12 cm2 ROI was usedto cover the entire area of the striatum plussome of the surrounding brain. To correct forthe activity from the surrounding brain andfor striatal activity emanating from non-fluorodopamine metabolites of 6FD, a ROIwas applied over each posterior temporo-parietal cortex and the activity recorded fromthis ROI was substracted from that of thestriatal ROI."Our method of total striatal sampling with a

large ROI minimises the partial volume effectthat may occur in the presence of striatalatrophy. Because of the partial volume effect,PET may underestimate the radioactivity con-centration in small structures as the counts aredistributed over a larger area than the originalstructure. However, despite the wide distribu-tion, the counts are conserved26 so a relativelylarge ROI will measure total radioactivity inthe structure of interest."The graphical method requires correction

for the decreasing availability of 6FD to thestriatum as it is metabolised in the periphery.In particular, allowance must be made for theaction of catechol-O-methyl transferase on6FD to form 3-0-methyl-6FD (3-OMFD).We measured the plasma concentration of 3-OMFD by the method described by Boyes et aland calculated the ratio of3-OMFD to 6FD ineach blood sample.27 In previous studies, weexpressed the increase of this ratio with time asthe slope of a straight line calculated by regres-sion analysis." However, inspection of the data

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Snow, Bhatt, Martin, Li, Calne

Figure 1 FD uptakeconstants plotted againstagefor five patients withWilson's disease and 18normal subjects. Theregression line isfor thenormal subjects (r = 05p < O OS); the brokenlines mark 90% confidencelimitsfor prediction ofindividual values.

1*i

0O-C

4)

L-

(10

0.'

0-l

0O.

0 individual values were placed at 90% to test ourhypothesis of a low 6FD uptake rate constant at

0 * A....a probability of 0 05 (one-sided). Patient 3 hado o°.L .... a normal 6FD uptake rate constant; patients 1__o°° 00 and 4 had constants just below the confidence

06 0 0 limit of the control group; the constants of0.... o 0 Opatients2and5fellwellbelowtheconfidence

4A* *------- A.. . ^o.. limit of the control group.Analysis of covariance revealed a significant

Adifference between the normal andWD groups

2 A (p = 0-001), with homogeneity of the slopeswith age (p = 0 88).28

0 __Selected PET and MRI images that best20 30 40 50 60 illustrate the abnormalities seen in each patient

Age are shown in figs 2 and 3. The distribution ofabnormal findings on MRI was similar to those

.. .~. .. reported in previous studies (table 2).ireveals that this increase is not necessarilylinear. We have improved upon this method bycalculating the proportion of total bloodradioactivity due to 6FD at a series of timesafter tracer administration. We used theseproportions to correct the blood time-activitycurve and thus determine the true input func-tion.MRI was performed on a Picker Inter-

national Cryogenic MR2000 operating at 0-15Tesla. Twelve contiguous 1 cm thick sliceswere obtained using a double-echo spin echo(SE) sequence with repetition times (TR) of2045 ms and echo delay times (TE) of 40 and120 ms, and an inversion recovery (IR)sequence with a TR of 2450 ms, inversion time(TI) of 400 ms, and TE of 40 ms.This study was approved by the UBC ethics

committee, and informed consent was obtainedfrom all participants.

ResultsBecause of the influence of age on the 6FDuptake rate constant, we plotted the constantsagainst age -to compare the patients with thecontrol group (fig 1). Limits for prediction of

Figure 2 6FD PET images infive patients with Wilson's disease and a normal subject(age 40years) for comparison. Figures on the scale are radioactivity concentration inarbitrary units. The images represent 30 minutes of emission data acquired during thesecond hour after administration of the tracer.

DiscussionWe have shown that the nigrostriatal dopamin-ergic pathway is variably damaged in WD. Thevariation in 6FD uptake.rate constants betweenour patients is consistent with the clinical,radiological and MRI heterogeneity of thedisease.29 Our results reinforce the concept thatWD is a multifocal process.

Previous studies have suggested that anigrostriatal dopaminergic lesion may bepresent in WD. Necropsy analyses in twopatients found reduced striatal dopamine andtyrosine hydroxylase.9 0 Another study detec-ted reduced cerebrospinal fluid dopaminemetabolites in one patient with WD, while asibling with asymptomatic disease had normalconcentrations.30 Case reports have described arange of responses to levodopa in therapeutictrials.31 32 The variation may derive from dif-ferent methods of study, or from differentdegrees of dopaminergic deficit. PET providesa more direct assessment of in vivo dopaminesynthesis and storage than previous methodshave allowed.The PET images of our two patients with

considerably reduced 6FD uptake suggest thatthe main loss of striatal radioactivity accumula-tion is in the region of the putamen withrelative sparing ofthe caudate (patients 2 and 5,fig 2). This. finding is consistent with nec-ropsy observations suggesting preferentialinvolvement of the putamen in WD.3

Despite the normal routine liver functiontests, it is theoretically possible that hepaticdysfunction associated with WD may haveincreased plasma amino acid-levels which mayin turn have competed with 6FD for transportacross the blood-brain barrier. We investigatedthis by comparing the background activity(corrected for the dose of radioactivity injected)of the WD patients with the backgroundactivity of the control subjects. There was nosignificant difference [WD 0-22 (0 052), con-trols 0 21 (0 056), arbitrary units of radio-activity within the posterior temporo-parietalcortex ROIs]. Previous studies of 6FD PETwith simultaneous amino-acid infusions inhumans33 and monkeys (unpublished observa-tions) have shown a decrease in backgroundradioactivity. Thus we conclude that thedecrease in striatal 6FD uptake seen in our

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The nigrostriatal dopaininergic pathway in Wilson's disease studied with positron emission tomography

Patient 3

z irXc 3 A IaI1 LIrt LhIEEl 7 . lVIlXtM eL' Strtiata l aiI b 1 rInaILI lt l'eS LLS.t- i'd?'Il in thc

ItaleF. P aItienlt 1 -Spin leCh0 SIE .PL1EIa l t2--SE; PLatient 3 I-nz'eirszreoLoc-7rv IJRPatient 4 -IR; Patient 5-,SE

patients did not derive from competition at theblood-brain barrier.Among the patients with abnormal PET,

there were quantitative differences in the 6FDuptake rate constants that may explain some ofthe clinical features ofWXD. Clinically, patients1, 4 and 5 had predominantly Parkinsonianfeatures. On PET, patients 1 and 4 had mildlyabnormal 6FD uptake rate constants, and on

MRI both had mild striatal abnormalities.Thus their Parkinsonism may have derivedfrom a combination of damage to dopaminergicnigrostriatal pathway neurons and damage to

non-dopaminergic neurons intrinsic to thestriatum.34 In contrast, patient 5 had a mark-edly reduced 6FD uptake rate constant withoutMRI abnormalities of the basal ganglia. Thelesion that produced her Parkinsonism was

probably confined to the nigrostriataldopaminergic pathway.The findings in patient 5 also show that there

may be dysfunction of the dopaminergic path-way in WD without lesions detected by MRI.This is in accord with PET studies ofWD thatdemonstrate decreased glucose metabolismpreceding radiological changes.35 We do not

Table 2 MRI Findings

Patient Striata Midbrain Cerebral Hemispheres

1 Increased signal from putamen Atrophy N2 Caudate atrophy Atrophy Mild atrophy

Increased signal from caudate and putamen Increased signal from the colliculi Increased signal from periventricular white matter3 N Atrophy Mild atrophy4 N Atrophy Atrophy5 N Atrophy Atrophy

No patient had focal MRI abnormalities in the region of the substantia nigra. N = no abnormality in the structure.

Patient 2

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Snow, Bhatt, Martin, Li, Calne

Figure 4 MRI imagethrough the level of themidbrain of Patient 2showing the midbrainatrophy and the increasedsignalfrom the colliculi(spin echo).

know if the dopaminergic dysfunctionobserved in our patients resulted from directdamage to the nerve bodies in the substantianigra, or from damage to the striatal nerve

endings followed by retrograde death of axons.Although MRI with a higher field strengthmay have revealed abnormalities in the regionof the substantia nigra in some of our patients,8such abnormalities would have neither confir-med nor quantified dopaminergic dysfunc-tion-this can only be revealed with PET in theliving subject.The dystonia of patient 2 was associated with

striatal abnormalities different from those ofthe Parkinsonian patients. Despite the markedreduction in her 6FD uptake rate constant, shehad no clinical Parkinsonism. On MRI therewas atrophy of the caudate and SE abnor-malities of the putamen that were much more

severe than in patients 1 and 4. These findingsare consistent with the proposal that selectiveloss of dopaminergic input to a relatively intactstriatum results in Parkinsonism, while des-truction of the putamen may cause dystonia.36"J M Walshe has suggested this pattern ofdisturbance in WD on pathological grounds.29The common experience that patients with thedystonic form of WD are less likely to respondto chelating therapy is consistent with thenotion that these patients have more extensivestriatal damage.

In summary, we have shown that nigro-striatal dopaminergic dysfunction is a featureof neurological WD. This dysfunction mayoccur without focal abnormalities on low-fieldMRI and may remain after many years ofpenicillamine treatment. In addition,previously undetected lesions of the dopamin-ergic system may explain some of the differen-ces in the neurological presentation of patients.The presence and persistence of these lesions

reinforces the importance of the early diagnosisand prompt treatment of WD.

We thank Sandra Cooper for her assistance with scanning as wellas the members of the UBC/TRIUMF PET team. Dr MichaelSchulzer assisted with statistical analysis. This study wassupported by the Dystonia Medical Research Foundation, theAmerican Parkinson's Disease Association, and the NewZealand Neurological Foundation.

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