the metabolic topography of parkinsonism

7/21/2019 The Metabolic Topography of Parkinsonism

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Journal of Cerebral Blood Flow and Metabolism The Inteational Society of Cerebra Blood Flow and MetaboismPublished b Raven Press, Ltd., New York

The Metabolic Topography of Parkinsonism

D. Eidelberg, *J R. Moeller, V Dhawan, P Spetsieris, S. Takikawa, T. Ishikawa,T. Chaly W Robeson, D. Margoulff, :S. Przedborski, and :S. Fahn

Departmet of Neurology, North Shore Uiversty Hospital/Corell Uiversity Medical College, Mahasset,*Departmet of Psychiat, New York State Psychiatric stitute, Columbia College of Physicias ad Surgeos,ew York, Departmets of Medicie ad Research, North Shore Uiversity Hospital/Corell Uiversity MedicalCollege, Mahasset, ad Departmet of Neurology, euroogical stitute, Coumbia College of Physicias ad

Surgeos, New York, New York, USA

Summary: We used [F]fuorodeoxygucose/posironemission omography FFDG/PET) and a saisicamode of regiona covariaion o sudy brain opographicorganizaion in parkinsonism. We sudied 22 paiens wihParkinsons disease (PD), 20 agemached norma vouneers, and 10 age and seve riymached paiens wih presumed sriaonigra degeneraion (SND). We used FDGPET o cacuae goba, regiona, and normaized meaboic raes for gucose GMR, rCMR, rCMR/GR).Meaboic parameers in he hree groups were comparedusing an anaysis of variance, wih a correcion for muipe comparisons, and discriminan anayss. The scaedsub proe mode (S SM) was appied o he combinedrCMR daase o idenfy opographic covariance proles ha disinguish PD paiens from SND paiens andnormas. GMR, rCMR, and rCMR/GR were norma in PD; caudae and eniform rCMR/GMR was reduced in he SND group < 0.01). SS M anaysis of hecombined group of paiens and normas reveaed a signican opographic proe characerized by increased

Received My 24 993; nl revision received Jnury 8994; ccepted Jnury 9 994

Address correspondence nd reprint requests to Dr DEidelberg Deptment of Neurology North Shore UniversityHospitl/Cornell University Medicl College 300 CommunityDrive Mnhsset NY 030 USA

bbrevatons used ANOVA nlysis of vrince; CT computed tomogrphy; dopmine 34-dihydroxyphenylethylmine;FDG [Ffluorodeoxyglucose; FDOPA Ffluoro-34-

dihydroxyphenyllnine; GMR globl metbolic rte for glucose; GSF globl scling fctor; H&Y Hoehn nd Yhr (97);MGP medil pllidum; MR! mgnetic resonnce imging; OMorbitometl; PCA principl-components nlysis; PD Prkinson's disese; PD group with mild PD (H&Y Stges III; PDgroup with dvnced PD (H&Y Stges IIIV; PET positronemission tomogrphy; rCMR regionl cerebrl metbolic rtefor glucose; rCMR ' leright symmetry index for rCMRin pired regions; ROI region of interest; SMA supplementrymotor re; SND stritonigrl degenertion; SSF subject scling fctor; SSF" SSF nd SSF SSF for Topogrphic Proles1 2 nd 3 respectively; SSF nd SSF SSF for CotrstProles nd 2 respectively; SSM scled sub prole model;SH subthlmic nucleus; UPDRS Unied Prkinson DiseseRting Scle 3.0.

meaboic aciviy in he eniform nuceus and haamusassociaed wih decreased acviy in he aera frona,paracenra, inferior pariea, and parieooccipia areas.ndividua subjec cores for his proe were significany eevaed in PD paiens compared wih normasand SND paiens < 0.001) and discriminaed he hreegroups. In he PD group, subjec scores for his facorcorreaed wih individua subjec Hoehn and YahrH&Y) scores < 0.02), and wih quaniaive rigidiy < 0.01) and bradykinesia < 0.03) raings, bu no wihremor raings. SSM anaysis of righ-e meaboicasymmeries yieded a opographic conras proe haaccuraey discriminaed midy affeced PD paiens(H&Y Sage I) from normas. Our ndings demonsraeha abnorma opographic covariance proes exis inparkinsonism. These proes have poenia cinica appicaion as neuroimaging markers in parkinsonism. KeyWords: F]FuorodeoxygucoseMeaboic opogra

phyParkinsonismPosiron emission omographySriaonigra degeneraion.

Although the primary biochemical pathology ofParkinson's disease (PD) is localized to the substan-tia nigra and its dopaminergic projections (Bern-heimer et aI., 1973), lesions of the presynaptic ni-grostriatal 3,4dihydroxyphenylethylamine (dopa-mine) system produce widespread abnormalities inregional cerebral metabolism and blood fl ow

(Wooten and Colins, 1981; Crossman et aI., 1985,1990; Porrino et aI., 1987; Palombo et aI., 1990).Studies in patients with PD using positron emissiontomography (PET) have suggested increass inbasal ganglion metabolism (Martin et aI.: 1984;Rougement et aI. 1984; Wolfson et aI., 1985; Edel-berg et aI., 1990), as well as decreases in inferiorparietal and global metabolism, especialy in pa-tients with dementia (Kuhl et aI., 1984; Peppard etaI., 1990; Schapiro et aI. 1993). Nonetheless, re-gional and global metabolic changes have not beenfully reproducible across study populations, and the


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D EIDELBERG ET AL

relationship of these metabolic changes to independent indices of disease severity has not been closelyexamined

is generally recognized that many of the behavioral manifestations of normal and pathological nervous system function are subserved by topograph

ically distributed networks of interacting brain regions (eg, Mesulam, 1981) These networks maye epresented as patterns of covariation amongspatially distributed brain regions and can be altered by behavioral activation or the presence ofdisease Specifically, normal regional covariancepatterns may be disrupted by the presence of localized pathology such as that occurring in neurode-generative disorders such as Alzheimer's diseaseand PD Several approaches have evolved to identify and quantify these regional interactions Principalcomponents analysis (A) has been used inthe analysis of PT data to contrast groups in the

same resting state (eg, Moeller et aI, 1987; Rottenberg et aI, 1987; idelberg et aI, 1990; Sackeimet aI, 990) and, more recently, in brain activationparadigms (McLaughlin et aI , 1992; Friston et aI,1993) As extract multiple independent components that, singly or in combination, account for themajority of the variance in the regional PT data

These principal components or topographic covariance proles can be construed as distributedneural networks The scaled subprofile model(SSM), described by us previously (Moeller et aI,1987 Moeller and Strother, 1991), applies A tocombined popuations of subjects (e g, patients and

norma control subjects) blind to subject groupingsSSM extracts those principal components acrosswhich there is maximal regional variability achtopographic prole is associated with an individualsubject score that quanties the extent o which thetopographic profile is manifested by he subjectSSM analyses have been applied previously to functiona imaging data from a variety of neurodegener-ative and psychiatric disorders (Rottenberg et aI,1987 Anderson et aI, 1988; idelberg et aI, 1990;Sackei et aI, 1990, 1993)

n a preiminar attempt to identify abnormal regional covariation patterns in PD, we reported anSSM analysis of F]uorodeoxyglucose (FDG)PT data from 14 patients with PD and 18 normalcontrol subjects (idelberg et a, 1990) The resultssuggested the presence in PD of abnormal topographic proles characterized by covarying basalganglia and thalamic increases in metabolism, mostevident in an analysis of rightle metabolic asymmetries ndividual subject scores for these prolescorrelated signicantly with independent measuresof disease severity and with striatal F]uoro3,4

J Cr Bl lw Mta Vl 14 5 1994

dihydroxyphenylalanine (FDOPA) uptake rate con-stants This study was limited by the low resolutionof the PT tomograph, and basal ganglia metabolicactivity could not be subdivided into smaller subregions, such as the caudate and lentiform nuclei naddition, several of the paients with PD received

levodopa at the time of the PT study and the nor-mal control subjects were not agematchedn this study we sought to validate and expand

upon the previous ndings by examining FDG/PTdata derived from a larger, entirely new cohort ofmedicationfree PD patients and agematched con-trols using a higherresolution tomograph Topo-graphic proles from the new population were com-pared with those derived previously To assess thepotential of these profiles to serve as disease-specic markers, we correlated the individual sub

ject prole weights with independent clinical ratingsacross a broad range of disease severity We also

explored he potential for early disease detection byperforming discriminant analyses between normalsand patients at a sage of mild, early disease

Another aim was to explore the broader applica-tion of SSM in functional imaging studies of theakineticrigid movement disorders We have reported previously that striatonigral degeneration(SND) (Adams et aI, 1964), a parkinsonian syn-drome clinically resembling PD (Fearnley and Lees,1990), is associated with basal ganglia hypometab-olism, which distinguishes it from its classical drug

responsive counterpart (idelberg et a , 1993) Byadding a sample of patients with SND to a com-

bined sample of agematched normal control sub-jects and age and severitymatched patients withPD, we sought to determine whether SND was associated with a different topographic prole thanPD or whether the same topographic proles wereaffected in both parkinsonian disorders n addition,this threegroup anaysis allowed us to explore theapplicability of SSM analyses in the dierential di-agnosis of clinically similar but pathologicaly dis-crete neurodegenerative disorders

MATERIALS AND MEHOS

SubjectsThe following subjec groups were sudied wih quan

iaive FDGPETNormal Subjects We sudied 0 normal voluneer sub

jecs (10 m en and 10 women; mean age SD 470 171years) recruied by adverisemen among he hosp ial personnel of Norh Shore Universiy HospialConel Universiy Medical College and he spou ses of PD paiens inlocal suppor groups The following excusion crieriawere used: (a) a hisory of neurological or psychiaricillness; (b) prior exposure o neurolepic agens or druguse; (c) a medical hisory of hyperension cardiovascular


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THE METABOLIC TOPOGRAPHY OF PARKINSONISM 5

disease, and diabetes meitus; and (d) an abnorma neuroogica examination

Patiets with PD We studied 22 idiopathic PD patientswithout dementia (12 men and 10 women; age, 579 114 years) A diagnosis ofPD was made if the patient had"pure parkinsonis m without a history of known causative factors such as encephaliis or neuroeptic treatment; did not have eary dementia, supranucear gaze abnormalities, or ataxia; and did have a convincing response to levodopa [20% change in composite UnedParkinson Disease Rating Scae (UPDRS) 30 motorscores (items 1931) (Fhn et a, 187)] In a patientsfamily histories were negative for neurodegenerative inesses Magnetic resonance imaging (MRI) was performed in 18 of 22 patients and computed tomography(CT) scanning in 4 of 22 patients Highed strength Tweighted MRI (echo time, 80 ms; repetition time,1,500 ms; eld strength, 10 T) discosed a normapuamenal signal in al cases sudied Visually evidentcortical or subcortical atrophy was absent in al patients

Patients were seected with a range of cinica severityaccording to their Hoehn and Yahr (H&Y) (1967) ratingsFive patients were selected in each of H&Y Stages I-IV

and two patients in H&Y Stage V (Paient representationin the atter category was imited by the technica diculty associated with scanning markedy disabed advanced patients) To facilitate comparison s between midand moderatesevere patients, the PD group was subdivided into two subgroups (Table 1): The mid group (PD:H&Y Stages III) consisted of 10 patients (5 men and 5women; age, 530 99 years; mean disease duration, 44 30 years) The advanced group (PD: H&Y SagesIIIV) consisted of 12 patients (7 men an d 5 women; age,619 112 years; mean disease duration, 115 61

TABLE 1.

Ptient No. Durtion H&Y(ge; yr) (yr) Stge BK

1 (45) 6 I 22 (48 7 I 23 (48 5 I 34 (61 1 I 35 (69 7 I 26 (41 1 II 37 (47 6 II 18 (49 4 II 59 (53 ) 1 1 II 7

10 (69 1 II 51 1 (45 5 III 1 312 (57 8 III 713 (62 3 III 8

14 (71 23 III 41 5 (72) 1 1 III 216 (41 1 1 IV 1 11 7 (62) 14 IV 1 518 (63 7 IV 719 (63 17 IV 1 120 (64 13 IV 821 (60 9 V 2022 73 24 V 8

years) The cinica characteristics of these PD patientsare given in Table 1

Patiets with SND We studied 10 patients (8 womenand 2 men; age, 618 69 years) with clinical ndingscompatibe with SND (Fearnley and Lees, 1990) Thecinical characteristics of these 10 SND patien ts and theircase histories have been reported by us elsewhere (Eidelberg et a, 1993) A patients presented with progressiveimb rigidity and bradykinesia associated with early impairment of baance and gait and without ataxia, supranucear gaze abnormaities, or dementia Motor symptoms were refractory to evodop a and dopamine agonists(daiy dose, 1,000 mg levodopa equivalents; 15%change in composite UPDRS motor scores) Transient orminima levodopa responses were evident in four of thesepatients Six of the SND patients were on chronic leodopa therapy up to the time of PET imaging; the remainder were o medication for at least 2 weeks prior to s canning MRI was performed on eight patients and CT ontwo patients Highed strength Tweighted MRI (echotime, 80 ms; repeition time, 1,500 ms; ed strength,10 T) discosed patchy putamenal loss of signa in fourof eight patients Mid brainstem atrophy was noted in

one patient; cortical atrophy was absent in all patientsMetaboic data on he 10 SND patients, 15 of 22 PD patients, and 10 of20 normal subjects have been repo ed byus previousy (Eideberg et a, 1993)

PETThe patients and vounteers fasted overnight prior to

FDGPET scanning In all PD and SND patients, all antiparkinsonian medications were discontinued at least 12h before PET was conducted At the time of PET study,a PD and SND patients were rated quantitatively ac

PD patiets

UPDRS rting

T R A Medition()

2 1 3 42 0 4 1 40 2 5 1 42 1 6 1 42 1 5 1, 41 4 4 36 4 4 35 1 -4 51 2 -4 1 2 43 5 5 3 41 2 4 1 20 4 1 1 20 8 2 1

0 1 2 1 2 3 40 2 2 1 2 3 48 1 3 1 3 41 9 3 1 2 45 9 2 1 2 46 5 2 11 2 1 1 2 41 1 8 1 1 2 46 7 2 1 2

a UPDRS ummed linil ore for brdykinei (BK), tremor (T) nd rigidity (R). Aymmetry (A) i the rightle diffeene in theum of the individul unilterl limb oe . Poiti ve nd negtive vlue repetively denote right- nd left-ided linil pedominne.

1 Levodoprbidop; 2 dopmine gonit ; (3 ntiholinergi; (4 monomine oxide inhibitor; (5 none.

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cording to the H&Y and UPDRS scaes PET studieswere performed using he Superpett 3000 tomograph(Scanditronix Essex, MA, USA) The performancecharacteristics of this instrument have been describedesewhere (Robeson et a, 1993) This fourring BaFtimeofight, whoebody tomograph acquires 14 PETsices with Zaxis transation Each sice is 8 mm thickand reconstructed with a transaxia resoution of 8 mm

(fu width at hafmaximum) Ehica permission for thesestudis was obtained from the Instiutiona Review B oardof orth Shore University Hospita/Corne UniversityMedica Coege Written conse nt was obtained from eachsubect foowing a detaied expanation of the procedures

Patients were positioned in the scanner n a custommoded headrest (Apha Crade Smithers Medica, Tamadge, OH, USA) (Kearfott, 1984) with threedimensiona aser aignment wih reference to the orbitomeata (OM) ine A cyindrica tube ed with Ge waspaced in the ed of view to provide interna caibrationfor each sice A studies were peformed with the subect 's eyes open in a dimy it room and minima audiorystimuation FDG was produced using the radiochemica

synthesis of Chay and coeagues (1990) Subecs received 510 mCi of FDG by intravenous inection Thetime course of pasma F radioacivity was determinedby samping radia arteria bood foowed by centrigation PET images were reconstructed with a correcionfor tissue attenuation of 511 keV of radiation measuredwith an externa Ge ring source PET reconstructionswere aso corrected for random coincidences, eectronicdead time, and tissue attenuation A singe scaar correction was used to compensate for scatter effects in transmission, crosscaibration, and emssion scans (Robesonet a, 1993)

We cacuated goba and regiona metaboic rates forgucose (GMR and rCMR, respectivey) in a FDGPET studies using autoradiographic scans (Pheps et a,

1979) acquired for 20 min beginning 35 min postiection,with estimated mean norma rate con stants [k 01056,k 01584, k3 00904 k was fixed at 00068 (Dhawanet a, 1989; Eideberg et a, 1993; Robe son e a, 1993)]To faciitate comparisons with our previous metaboicdata, we chose a umped constan of 042

Regionofinterest (ROI) anayss was performed on256 256 PET reconstructions using a SU microcomputer (490 SPARC Server Sun Microsystems, MountanView, CA, USA) with ScanVP Soware (Spetsieris et 1993) To compare regiona vaues with those reported by us earier (Eideberg et a, 1990, 1993), wedened 26 (13 per hemisphere) standardized cortica andsubcortica gray matter ROIs and two cerebear and twobrainstem ROIs ROIs were dened interactivey on reconstructed PET sices by visua inspection with reference to a standard neuroanatomica atas (Taairach andTournoux, 1988) and MRI or CT when avaiabe MeanROI size ranged from 40 pixes for the caudate nuceus to350 pixes for the atera fronta and tempora corticaregions (1 pixe 4 mm

) To reduce partia voume ef

fects, we cacuated "peak rCMR vaues by averagingthe upper 20% of ROI pixe vaues (Rottenberg et a,1991) Whenever anatomica regions stradded contiguousPET sices, the rCMR was cacuated by weightingcomponent ROI vaues by the number of threshoded pixes on each sice The GMR was cacuated as he mean ofthe rCMR vaues weighted by the tota number of

J Cereb Bl lw Metab Vl 14 5 199 4

hreshoded pixes in each ROI To reduce intersubectvariabiity, regiona metaboic measurements were normaized by goba vaues (r CMR/GMR) We aso cacuaed a righ-e asymmetry index (rCMR) for eachpaired region dened as ( R)/( + R) 100%, whereL and R refer to e and right homoogous rCMR vaues, respecivey

Statistical analysesGlucose Metabolism The foowing statistica proce

dres were empoyed for beweengroup comp arisons (a)We compared GMR and rCMR and GMRnormaizedreiona vaues (rCMR/GMR) for the various cinicagroups usin anaysis of variance (AOV A) foowed bypost hoc group comparisons using the Tukey-KramerHSD adustment (Winer, 1971) This procedure was apped separatey to a the individua regiona vaues (30rCMR and 30 rCMR/GMR measurements) and to theGR (b) To idenify the regiona vaues that maximaydiscriminate the various groups, we empoyed stepwisediscriminan anaysis using the est associated withWiks (Anderson, 1984) The vaues are reported

incorporating the B onferroni correction for the number ofregiona comparisons Differences between groups wereconsidered signicant when comparisons exceeded 95%confidence imits < 005)

In this study we performed wo separate sets of betweengroup comparisons In the first anaysis, we compared he metaboic parameters derived for the entire typica PD (n 22) and norma contro (n 20) sampes Inthe sec ond anaysis, we performed a threegroup comparson of the metaboic parameters measured in the entireSND sampe (n 10 mean age, 618 69 years meanH&Y score 35 08), an age and severitymatchedsubset of the PD sampe (Patients 11-18, 22, and 23; n 10 mean age, 606 108 years mean H&Y score, 37 08), and an approximatey agematched norma contro

sampes (n 10 mean age, 576 126 years) Identicastatistica procedures were carried out for each set ofbetweengroup comparisons

M: Methodology. To determine whether specificpaterns of regiona metaboic covariation distinguishedthe groups, atien and norma contro rCMR datasetswere anayzed using SSM The mathematica propertiesof this mode, its statistica assumptions, and its computaiona procedures have been described esewhere(Moeer et a, 1987 Moe er and Strother, 1991; Sackeimet a, 1993) This statistica mode propose s that, for eachsubect, each regiona rCMR vaue is comprised of twobasic eements (a) A diffuse or regionaindependentscaing factor (goba scaing factor GSF) moduates orscaes a regiona vaues for a given individua The GSFis simiar to the GMR, but the contributions of the topographic proes are removed in the cacuation of theGSF (b) Independent sets of topographic proes correspond o different paterns of covariance among brainregions The contribution of a particuar brain region to atopographic profie, ie, its reative importance in thecovariance reationships within the proe, is quantedby its regiona weight in the corresponding topgraphicproe Therefore, the topographic proe is a vector ofregiona vaues representing the covariance reationshipsamong the brain regions Because different individuasmanifest these reationships to greater or esser degrees,the SSM computes a subect score (subect scaing factor


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THE METABOLIC TOPOGRAPHY OF PARSONISM

SSF) to quantify individua differences in manifesingeach topographic proe

A SSM parameters were derived by appying themode to the data from the tota sampe, bind o groupmembership The computations invoved subtracingfrom ach subects regiona vaues the mean vaue ateach region, determined across he tota sampe Thesedierence scores produced the approximation to the sub

ec t region variance A PCA was performed on thetransposed covariance matrix of these dierence scoresto extract a set of principa (unrotated) components Theregion weighs on each principa component described atopographic covariance proe The subect scores for aprincipa component (PCA scaars or SSFs) quantified theextent to which the topographic pattern was manifestedby the individua subect The number of principa components to retain was determined by appying the Screetes (Stevens, 1986) to the set of eigenvaues and by examining the extent to which the SSFs accounted for thevariance in GMR vaues The GSF was computed foreach subect using mutipe regression anaysis to predictgoba mean rCMR vaues on the basis of the SS Fs TheGSF corresponded to the residu between predicted and

obained vaues Adding the intercept erm to the residuas produced the na form of the GSF n the originarCMR units

In addition, a separate anaysis of right-e metaboicasymmetries was performed usng the rCMR metaboic asymmetry measures This procedure is computationay idenica to the SSM anaysis of the hemisphericrCMR data described above However, by usingrCMR vaues, this SSM anaysis identifies topographic contrast proes represe nting covariance patternsof regiona metaboic asymmet whose contribution mayvary across the subects anayzed within he tota sampe

To determine whether the groups differed on the SSMparameters of GMR (GSF) or topographic organiztion(SS Fs), the same ANOV A procedures and discrimnant

anayses were appied s d escribed above for the rCMRdatum anaysis The p vaues were corrected for mutipeSSF and GSF comparisons using an ordered Bonferroniprocedure with ranking by eigenvaue (Ro sentha and Rubin, 1984).

SSM: Clinical Correlations and Topographic ProleComparisons. Clinical-metabolic correlations Personproduct-moment correations were co mputed to examinethe reationship between the cinica and he metaboicmeasures The foowing cinica parameters were used inthese correations: H&Y scores, individu UPDRS motor scores for tremor, rigidity, bradykinesia, p osture, andgait, and a composite motor score defined as the sum ofitems 19-31 in the UPDRS (Fahn et a, 1987). We asocacuated a imb asymmetry index defined by rightedierences in individua imb UPDRS scores (Eideberget a, 1990) Bec ause these cinica sc ores may be coseycorreated within individua subects, we performed apairwise correationa anaysis of the individua scores toidentify interreated subsets of scores (Eideberg et a,1990). H&Y scores, composite UPDRS motor scores,mean vaues of intercorreated subsets of scores, and individua UPDRS scores were correated with the foowing metaboic measures: (a) rCMR and rCMRGMRfor a 30 right and ehemisphe ric and brainstem ROIs;(b) SSFs for the various topographic proes; and (c) thegoba metaboic measures, GMR and GSF The p vaueswere corrected for the number of independent cinica

metaboic correations performed and were consideredsignicant when


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TABLE 2 rCMR1 and GMR mg min-I gI)

Mea SD

Nomal PD1 PD SND(n 20 (n = 10 (n = 12 n 10

Ceebellm 7.57.1 1 6 .93 (1 . 14 6. 51 (0.94 6 .62 ( 1 .0 1 Po 5.11 (0 .90 4. 85 .06 4.38 (0.68 4.40 (0.60

Midbai 5.89 (1.24 5 .75 ( 1 . 18 4.54 (0.83 5.09 (0.68Cadate 7.89 (1 .21 7 .28 (1 .03 6.2 1 (1 .07 5.96 (0.85Letifom 8.61.19 8 .20 (1 .16 7.36 (1.30 6 . 1 5 ( 1 .06Thalam 7.78 (1 .14 7.54 (1 .04 6.38 (0.78 6.04 (1.02Med tempoal 6.09 (1 .15 5 .64 (1 .01 4.88 (0.89 5 .95 (1 .05Lat tempoal 7.54 (1 .3 1 7 .27 (1 . 22 5. 55 (1 .29 6. 17 (0.69Opeclm 8. 75 (1 .44 8.04 (1 . 17 6.40 (0.87 6.45 (0.78Sp tempoal 9.06 (1 .55 8.55 (1.22 6 .95 (1 . 10 6.03 (0.76Med fotal 8.02 .33 7. 34 .39 5. 87 (0.89 5. 63 (0.71 Lat fotal 8.78 (1 .52 7.89 (1 .36 6.2 1 (0.92 6.07 (0.68Calcaie 10.24 (1.62 9 .30 ( 1 . 8 1 7.58 (1 .50 6.63 (0.75Ce 9 .9 1 ( 1 . 6 1 8. 84 (2.09 6.96 (1.24 6.77 (0.84If paietal 8 .5 1 ( 1 .28 7.87 (1.30 6 .24 (1 . 1 1 7 .06 (0 .86Paacetal 7 .85 ( 1 . 14 6.42 (2.53 5.78 (1.04 7.60 (0.85GMR 8.35 (1 .25 7.82 (1 . 22 6. 41 (0.89 7. 02 (0.70

Med, medial; lat, lateal; p, peio; if, ifeio

accounted for 437 of the variance in GMR Thisindicated that a substantial portion of GMR variability was due to individual differences in thesemajor topographic effects When the topographiceects were removed, a regionindependent globalmeasure (GSF) was calculated The PD and normalgroups did not differ in GSF, suggesting that thetwo groups differ primarily in the representation ofthe topographic proles

The region weights on the three signicant topographic proles are presented in Table 3. SSF val

ues for the various proles were transformed andoffset to a mean of zero for the normal control pop

ulation (Scalar adjustments in subject scores do notinuence betweengroup statistical comparisons orclinical correlations because all members of thesamples are shied equally) Thus, individual SSFswere interpreted relative to an adjusted metabolicbaseline dened by the normal control populationAdditionally, the polarity of the proles was oriented so that the mean SSFs for the PD group hadpositive values and positive subject

xregion pro

TABLE 3 Region weights on the three bihemispheric topographic proles

Pole Pole

2 3 2 3

Po 0.79 0.40Midbai 0.42

Le hemiphee Riht hemiphee

Ceebellm 0.86 0.69 66 0 .9 1Cadate cle 0.46 0 . 1 2 0 . 1 1 0.84 0.43 0.24Letifom cle 0.78 0.62 9 0.70 0.88Thalam 0.19 0.35 0.78 0.10 0.31Med tempoal 0.27 0 .8 1 . 0.79Lat tempoal . 0.58 .

Opeclm 0.55 0 . 14 0.48 0.04 Sp tempoal 0.18 0.06 0.75 0.49 0.1 5 0.08Med fotal 0.74 0.13 0.65 0.23 Lat fotal 0.20 0.37 0.86 0. 13 0.59Occipital 0.29 0.18 0.42 0.28Paietooccipital 0.97 0.86 . If paietal 0.95 0.95 0.03 0.65 .Paacetal 0.60 9 0.79 0.47 69

The topoaphic prole wee idetied by SSM aalyi of bihemiphec CMR data fom acombied op of 22 PD patiet ad 20 omal cotol bject Poitive ad eative valeidicate eio of elatve metabolic iceae ad deceae, epectively Reio weiht 1 aeitalicized; thoe alo aociated with moto cotol etwok ae boldfaced Med, medial; lat, lateal;p, peio; if, infeio

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THE METABOLIC TOPGRAPHY F PARKINSONISM

les (Moeller and Strother, 1991; Sackeim et aI.,1993).

The following topographic proles were identi-ed in the analysis of bihemispheric rCMRJ data(n = 2)

Topographic Prole This topographic prole

20.7% variance accounted for; V AF) was charac-terized by increased activity of the cerebellum,pons, lentiform nucleus, and thalamus associatedwith covariate decreased activity of the lateral fron-tal, paracentral, and parietal association cortices.(Calcarine activity did not contribute to this covari-ance pattern, dening a reference point with whichto compare the activity of the other regions.) Anisometric display of this pattern is presented in Fig.1. Subject scores for this prole (SSF ) were signif-icantly higher for the entire PD group comparedwith the normals ( 0.001). The mean SSF wassignicantly higher in the PD subgroup compared

with the PD subgroup and the normal controls ( 0.01 for both comparisons) (Fig. 2 SSF discrimi-nated the PD group from the normals [1,40) =14.9, p 0.001], specifically separating the ad-vanced PD subset [PD vs. normal, 1,28) = 1.1,nonsignicant; PD vs. normal, 1,30 = 36.0, p 0.0002].

Topographic Prole This topographic prole15.9% VAF) was characterized by increased activ-ity in the calcarine cortex and in the inferior parietaland parietooccipital areas. This was associated withdecreased activity of the midbrain and medial andlateral temporal areas. Mean subject scores for this

prole (SSF) did not differ between or discriminatethe PD and the normal groups.

Topographic Prole This topographic prole10.4% V AF) was characterized primarily by de-creases in medial frontal and paracentral activityassociated with increased parietooccipital and tem-poral lobe activity. Mean SSF values did not differin the two groups.

The following topographic contrast proles (Ta-ble 4) were identied in the analysis of the regionalasymmetry (rCMRJ) data (n = 42)

Contrast prole This contrast prole 14 0%V AF) was characterized by thalamic asymmetriescovarying with reciprocal polarity with asymme-tries in the paracentral cortex. Mean subject

weights for this contrast prole (SSF ) were signif-icanty higher than normal for the H&Y Stage pa-tients ( 0.02) but not for PD patients with moreadvanced disease (Fig. 3). SSF values discrimi-nated H&Y Stage patients from normals [1,23)= 25.5, p 0.0002] correctly identifying 5 of 5H&Y Stage patients and 18 of 20 normals. (Thetwo misidentied normals were aged 27 and 43

years.) SSF discriminated H&Y Stage patientsfrom those with more advanced disease less accu-rately [1,20) = 4.9, p 0.05].

Contrast prole This contrast profile 9.6%V AF) was characterized by thalamic and lentiformasymmetries covarying with reciprocal poarity

with asymmetries in the caudate nucleus. Meansubject weights for this contrast prole (SSFd didnot differ or discriminate among the normal and PDgroups.

SM clinical correlations and toograhicrole comarisons

Clinical-Metabolic Correlations lcose meta-olism. Correlation analysis of PD clinical scores re-vealed a strong pairwise correlation > 0.6, p 0.001) between individual UPDRS scores forbradykinesia, rigidity, and gait, composite UPDRSmotor ratings, and H&Y scores. Tremor ratings

were not signicantly associated with these otherratings ( 032) We therefore considered brady-kinesia, rigidity, and gait UPDRS scores to repre-sent a discrete subset of interrelated clinical ratings,designated subset A. n the PD group, GMR coe-lated negatively with H&Y scores (r = 0.58, p 0 01, composite UPDRS motor ratings (r = 0.56,

p 0.01), subset A mean ratings (r = 0.60, p 0.01), and individua UPDRS ratings for bradykine-sia = 0.63, p 0.005) and rigidity (r = 0.52,

p 0.05). GMR did not correlate with ratings fortremor, patient age, or disease duration ( > 0.1 forall correlations). n the PD group, regional meta-

bolic measures (rCMR and rCMRJ/GMR) didnot correlate with age, H&Y scores, or any of theindividual or composite ratings comprising theUPDRS ( > 0.1 for all correlations).

M descritors. n the PD group, GSF failed tocorrelate with clinical severity measures. This sug-gests that the GMR correlations were due primarilyto the contribution of topographic rather than globaleffects. n PD patients, SSF correlated signifi-cantly with age (r = 0.49,p 0.04), H&Y ratings (r= 0.61, 0.02), composite UPDRS motor rtins = 056, p 0.03) , and subset A mean ratings (r 0.63, p 0.01), as wel as with individual UPDRSratings for bradykinesia (r = 0.56, p 0.03) ndrigidity r = 0.62, p 0.01) (Fig. 4 No coelationwas evident between SSF values and tremor rat-ings (r 0.06) or disease duration (r 0.38). Nei-ther SSF nor SSF vaues correated with any ofthe clinical measures ( > 0.2 for all correlations).SSF values, obtained from the asymmetries nl-ysis, correlated with limb symmetry scores (r =0.53, p 0.04). SSF values did not coelte

with this parameter.

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B

J Cr Blood Flow Mta ol 1 4 No.5, 1994

. EIELBERG ET AL .

G Isometric display (Spetsieris et aI, 1993 of the regionweights for Topographic Profile1 n representative transversebrai slices acquired approximately 4 mm 6 mm Band 7 mm C above the OMlin The insets (lower lft) indicate the positons of th midlins of these transverse sliceson a standardized parasagittal

twodimensional display Relati v hyp er met abo li sm (c ol orscae) of the entiform nuceiand thalamus is shown in Relative hypometabolism (gray

scal) of the lateral frontal inferior parietal, ad parietooccipital areas is evident in B andparacentral hypometabolsmin C


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THE METABOLIC TOPOGRAPHY OF PARKINSONISM

G C: see legend on page79

Topogaphic Pole Compaio. eproducibility To examine the reproducibility of these topographic proles across study populations, we cor

related the region weights on these patterns withthose derived in our earlier study of a differentgroup of PD patients and norma controls Eidelberg et al , 1990) Each of the three major topographic proles derived from bihemisphere analysiswas highly correlated betwee the two study popu

2

tl

2

ORML D

lations Topographic Prole 1, = 074; Topographic Prole 2, = 080; Topographic Prole 3, 078; p 00001 for all correlations) This indi

cates that the reported bihemispheric topographicproles are reproducible in different PD patientpopulations under varying tomographic imagingconditions Of the two signicant topographic contrast paterns derived through asymmetries analyses, Contrast Prole 1 alone was correlated in the

G Scatter diagram showing the SSF1scores (see text) in normals and in the P01() and P02 A subgroups Mean valuEs (:S)are displayed by vertical bars SSF1 values wresignificantly increased in the P02 subgroupcompared with the P01 subgroup and normals

J Cereb Blood Flow Metab Vol 14 No 1994

C


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D EIDELBERG ET AL

TAL Rei weihts the tw tpraphicctrast pres

ebellde

Lohled olL eolOcl eold olL olOccilPoocclI elPcel

019060

051

055001

055005

069050

010

Pole

084

06776

01030004006086030093

009

h oohc co ole we ided by SM aly o d o cobied o o PD ied 0 ol cool bjec Poiive d eve valedc h live lely o he e ol ebolc y e

e (ee ex) eo weh ;1 e ilicized; hoe lo ced wh oo cool ewok e boldced Med, edl; l, lel; , eio; i, ieio

o r = 071, p 001) Contr Prol n un uy not orrla t ty rol xtr n arlr data-

Cris f rkisi btyes SSM anal-y of obn grou of 10 SND atnt, 10g n vry PD n, an 10 ag- nol onrol rval r gnantoogr rofl counng for 576 of

ub x gon vrn Nr of t globl t-bol ur, GMR or GSF, ffr aong tr gou ( > 03 for ll oron) Rgiong on r jor toograi rofil gly orl rgion gh on thoonng r rol n n th to-gou nly (Toogra Prol 1, r = 076, p 0000 Toogr Prol 2, r = 086, p 00001Toogr Pol 3, r = 04, p 0005) Si-lrly, for r rol r gly or-rl vlu lul for ubjtxn in t ogrou nly (SSF

Ir =

07, p 00005 SSF, r = 088, p 00001 SSF

,

r = 0, p 000) Tu, aon of ondn knonn grou o h SSM nly dno nro n or oogri rol, nor or oogry of PDaoatdro rb bov

gu 5 ly SSF valu for of t oog rol ntf n o-bn r grou nly or ng PD,ND, n norl onrol grou Coarion of SSF fr r grou nat that PD and

J b l Flw M/ab Vl 14 14

SND ffr fro on anor n t olry nagnu of rrnaton of rol SSF1valu r gncantly grtr n PD grouoar to t SND grou ( 0001) SSF -rinat o arknonan grou [(1, 18) =32, p 0000], orrly infyng of 10 -

tint n a of t PD an SND lnl go-ri Mn SSF valu no ffr n hrgrou Mn SSF valu r no gnanlyffrn n t PD an SND grou Wou Bon-

frron orron for ll SSF coron, not an abnormal lvaton of SSF vlu nt SND grou ( 003), t rn ord nbnoral lvaton ( = 006) n PD grouT SSF abnoralti i not r gnan Bonfrron orrton

DSCSSON

n th rot dontrat ulty of PCAaro, cally SSM, n nly ofobn rgonl tbol a fro PD nn norl conrol W foun rroubl, -ntv t of toogra ovrn rol orrlad h ndnnt clnl ur ofa vrty n t ubqun uon, xlor t nrrtation of t toogra ro-l in th contxt of t nuroanoil norkratng to motor ontrol, a ll a hr ontlalablity n lncal rarh

The etblic ty f rkisisn t tuy of PD, SSM analy rvl -

jor ovaran ro (Toogra Prol 1) twa nd toographially by t ky nuroan-tomcal ln of th oor conrol yt Trol a charctrizd by larg otv rgongt for t lntifor nuclu, halu, on,n crblu n larg ngv rgon gtfor t latral frontal, arantrl, nd rtl a-ocation ara T oitl corx, "nutrlbran rgon unnvolv n ro (Gibb, 192), ha rgon gt nar zro an,rfor, ba onvnin rfrn ont forth otr rgonl valu Th rgon g on

c toograh rol, mulil by h ao-t SSF, onut t ontrbuton of t rolto ovrall norlzd bran tbol Trfor,t rgon g for Toogra Prol 1 y bntrrt a abolc nr or dr rl-ativ to th oital baln

T nng of nr bol n ln-for nulu n alu n PD onn rior rort fro xrnl nl ol ofarknoni n C]oxygluo uoo-grahc xrin , unlral ngorl lion


11/19


G 3 Scatter diagram showing the SSC1

scores in normals and P patients ( Meanvalues (S) are displayed by vertical barsThese values were significantly eevated in theHY Stage I group The discrimination line(dashed) correctly identifies all HY Stage I pa

tients and 1 of 2 normals

U

2

2

" : "l""""""&

f:

;

:

give rise to increased rCMR in the ipsilateral

globus pallidus (Kozlowsk and Marshall, 1980;Wooten and Collins, 1981; Crossman et aI., 985;Palombo et aI., 1990; Mitchell et aI., 1992) Meta-bolic change in the corpus striatum has been lessconsistent suggesting either unchanged (Wootenand Collins, 1981; Mitchell et aI., 1992), decreased(Kozlowski and Marshall, 1980; Schwartzmanne aI., 199), or increased (Palomb et aI., 1990)rCMR on the lesioned side. ncreased metabolismin the ventral thalamus has been a consistent nding(Kozlowski and Marshall, 1980; Crossman et aI.,1985; Palombo et aI., 1990; Schwartzmann et aI.,1993) These ndings have been considered as re-

ecting the release of the basal gangia from nigraldopaminergic inhibition. Specically, the loss of in-hibitory nigrostriatal dopaminergic projections re-sults in nctional overaction of the putamen, witha consequent increase in the ring of inhibitory af-ferents to the lateral pallidum. As rCMR isdetermined primarly by afferent synaptic activity

15

"C

2

90u> 6'i 3

NmalIIV

eh & ahr tg

(Aucker et aI., 1983), it is expected that lateral al

lidal metabolism should increase. The reduction ininhibitory afferents to the subthalamic nucleus(STH) from the LGP results in decreased STH me-tabolismin the face of increased neuronal actvtyin that region. STH excitatory projectons to temedial pallidum (MGP) thereby increase resutngin increased MGP metabolism. Smary, inhbtory

projections from the MGP to the ventral thalausalso increase, resulting in increased metabolis inthese thalamic structures as well.

The striking regional abnormalites demonstratedby autoradiography in experimental animal modelsmay be obscured in lowerresoluton human T

studies. A number of early PT studies demonstrated hemispheric asymmetries in basa ganglionmetabolism, with a bias toward metabolic ncrasescontralateral to the clinically more afcted limbs(Martin et aI., 1984; Wolfson et a., 1985) ocaidbasal ganglion hypermetabolism in bilatrally affected individuals was not consistently evdent n

G 4. orrelations in P patients etween UPRS rigidity ratings and SSF1scores A significant positive correlationr = 62 P < 1 was found etween

these two variables

o -

5 5

SSF

5 2 25

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D EIDELBERG ET AL

2

ee

2

Scatter diagram showing the subject 2scores for te three topographic pofiles SSF1; 8 SSF2; and C SSF3) identifie in a com-binedgroup SSM analysis of the 1 SND pa-

tients A 1 age and severitymatched PD pa- Ntients _, and 1 age-matched normal subjects e0. (See text) Mean vaues (SD) are displayed e by vertica bars. The discrimination line(dashed) based on SSF1 correctly identifies9 of 1 members of the SND group ad 9 of 1 members of the age- and severitymatche PDgrop.

2

2

Mee

-

2

-3

earlier PT studies (Kuhl et aI., 1984; Rougement etaI., 1984) but has been reported using modern tomographs of improved resolution (Blesa et al.,1991).

J Cereb Blood Flow Metab Vol 14 No5 994

.

I.. - .....

ORM

c'

1c'

ORM

- - - - - _

!

(8)

(C)

The inconsistencies in previous FDG/PT stud-ies may stem from inherent difculty in extractingquantitative measures of palidal metabolism fromthe larger entiform RO. ndeed, because of the


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THE METABOLIC TOPOGRAPHY OF PARKINSONISM 5

necessary spatial inclusion of the less consistentlyaffected putamen, pallidal hypermetabolism may

become obscured within the composite lentiformregional measurement. Lentiform hypermetabolismmay herefore be low in absolute terms and may notbe detectable using conventional statistical method

oloies. Additionally, our inability to quantify pallidal rCMR precisely may obscure possible clini-calmetabolic relationships that might exist between this measure and tremor (Perlmutter andRaichle, 1985).

Apart from the inherent physical limitations ofPT in he measurement of rCMRJ in small re-gions (Mazziotta e aI., 1981), PT datum analysisrequires statistical consideration of the mltiplicityof regional measurements compared betweengroups (Winer, 1971). n this report we have treatedte individual rCMRJ and rCMRJ/GMR measures as independent observations and have cor-

rected he associated p values accordigly. n keep-ing wih our earlier observations (idelberg etaI., 1990), we found no signicant differences inrCMRJ and rCMR/GMR between the PD andthe normal groups and no signicant clinical correlations with these variables, even without imple-menting the stringent Bonferroni correction. None-theless, we are cognizant of the effects of interregional covariation in PT data and have developedSSM as a means of quantifying these regional iter-actions (Moeller et aI., 198). SSM analysis husprovides an alternative to traditional statistical ap-proaches for the identication of small biologically

relevant signals (Sackeim et aI., 1993). By delineating independent topographic proles, SSM tech-niques can extract covariate functioal elementswithin anatomically large and functionally heterogeneous ROs. We associate the covariate lentiformand thalamic hyperfunction identified in Topographic Prole 1 with the hypermetabolism of thepallidum ad ventral thalamus demonstrated in theautoradiographic animal experiments.

n addition to the basal ganglionthalamus interaction, this topographic prole included abnormalcovariae interactions of the cerebellum and pons.These two interconnected structures, with the thal-amus, constitute a separate motor control systemoperating in parallel to the basal ganglion circuits(Brodal, 1981). ndeed, these two systems share acommon output to the primary and supplementarycortical motor areas. Although lesions of the ponsand cerebellum have not been demonstrated histo-pathologically i PD, these regions have been im-plicated in experimental rodent models of 1methyl4phenyl ,2, 3,6tetrahydropyridine eurotoxicity(Takada et aI., 1993 ) n addition, these regions may

be abnormally activated in the course of parkinso-nian tremor (Brooks et aI., 1992). Our data indicatethat subject scores for Topographic Prole 1 did notcorrelate with restingstate tremor and that ponto-cerebellar hypermetabolism can contribute to ab-normal brain topography in both tremulous and

atremulous PD patients. An SSM analysis compar-ing PD patients with and without tremor may behelpful in determining whether the pontocerebellarhypometabolism evident in Topographic Prole 1 ispart of a discrete tremorspecic network or whether it is a fragmet of a more generalized disease-related pattern.

Both basal ganglion and cerebellar subcorticalmotor systems exert their inuence by modifyingthe activity of the cortical motor areas. ndeed, Topographic Prole 1 identied hypofunction of several corical regions involved in motor control.Nonetheless, primary, premotor, and supplemental

motor ROs could not be accurately specied. Be-cause of intersubject variability in the cerebral convolutions and their relationship to local cytoarchi-tectue (e.g., Le Gros Clark, 1945; idelberg andGalaburda, 1984; Rademacher et aI., 1993), as wellas potential focal atrophy eects, deformations intoa common coordinate space (e.g., Fox et aI., 1988)may be inherently imprecise, especially without individual subject activation data. ThreedimensionalMR/PT coregisration may be somewhat more re-liable for primary sensorimotor localization (e.g.,Grafton et aI., 1991) but remains inexac for thesupplementary motor area (SMA), which is not con-

sistently dened by sulcal markings. To preservecorrespondence with te regional information de-rived in our previous study, we opted for similarlylarge ROs. Comparison with standard anatomical(ycleshymer and Schoemaker, 1911), architectonic (von Economo, 1992), and functional stereo-tactic (Talairach and Tournoux, 1988) atlases re-veals the lateral frontal RO to be composed largelyof elements of the lateral premotor cortex and the

frontal eye elds [areas 6 and 8 of Brodmann (vonEconomo, 1929)]. [The pixel conribution of primary sensorimotor cortex (area 4) to this RO isconsidered to be small (see Fig. B).] Similarly, theparacentral RO included medial superior frontal re-gions corresponding largely to the SMA !medialarea 6 or GFd (Talairach and Tournoux, 1988)].Thus, the reduced weights of these regions noted inTopographic Prole 1 is suggestive of diminishedactivity of the lateral premotor regions and SMA.Reductions in the activity of these regions are likelyto stem from overactive suppression of the ventralthalamic nuclei caused by excessive MGP inhbi-tory outow. As these cortical regions receive sub

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D. EIDELBERG ET AL

tntl ffrnt from th vntrl thalmu, upron of th thlmc nucl apt to rduc themtbolc ctvty of thr motor cortcl projctontrgt. Th ndng ar contnt wth vdncof rducd mtbolm n prmotor corx n primt modl (Plombo t I., 1990) and PET evi

dnc of rducd actvaton of th SA durng thepformnc of motor tk n PD patnt (nknt I., 1992 Plyford t I., 1992).

Th hmphrc contrt prol contin mnyof th rgonl lmnt ncludd n TopogrphcProl of th bhmphric nly. Boh gnfcnt contrt prol rect mtabolc aymmetr n th thlamu covryng wth aymmetr nothr octd motor regon. W found that the

rltonh of th thlmc ymmtr wth theothr rgonl ymmr w oftn of rciprocalolrty, .., rltv ncr n thlamc mtabolm wr octd wth rltiv dcra n the

mtbolm of th covr rgon. For xmpl, nontrt Prol thlmc ymmtr wr octd wth SA ymmtr of oppot polrty. Th rcprocl rlatonhp content wthth oot polrty of th rgion weght for thtwo tructur notd n Topogrphc Prol 1 of thebhmphrc nly. n ontrt Prole 2 a ngtv covrnc w obrvd btwn cudtend thlmolntform aymmtr. Th my mrror th ndng of cudt nd putmn metbolm octd wth pllidl mtabolc ncr, notd n veral utordogrphy tud(olowk nd Mrhll, 1980 Schwrtmnn t

I., 99).Th ndng of prtl hypofuncton omwha

urrng, th rgon i not aoctd wth motor control ym. W ntrpret thi ndng touggt second locus of pthology n the PD tudyml, nvolvng brn rgon mplctd n thelhmr d proc (.g., Fotr aI., 1984xby t I., 1985 Dur t I., 1986). Gvn thhtothologcl ovrlp btwn clcl ngrlwy body chng nd cortcl nurobrllry tngl thology n otmortm pcmn (Gbb,992) t reonbl tht nocortcl nvolvmntmy mct upon th mtbolc prol of PD patnt, clly tho wth mor dvncd d. ndd, hyomtbolm of th prtl octon cortc h bn rportd n PD ptnt

wth dmnt (uhl t ., 1984 Schpro t I ,99) ur dt uggt tht th cortcl changmy b nrbl from th prknonn droc, uggtd by th hgh ncdnc of cogntv dtrorton n th PD populon (yuxt I., 199). Furthr nvtgtion comprng dmnted nd nondmntd PD patnt with qunt

rb l lw Mtab Vl 14 1994

tatv nuropychologcl corrlton wll bnedd to elucidat the prc bologcl manngof thee metabolc chang.

Th topogrphe of th othr gncnt prolexracted n th analy hv no mmdt ntrpretton n th framework of nurontomcl

pahway relatng o motor control or h parknonan de proc. Furthrmor, th prolofferd no mpl rgonl rfrnc pont, uch the occptal cortex n Topogrphc Prol 1 by

whch to den topogrphc functonal dvton.Th rol of h othr prole n dnng th mtabolc topogrphy of parknonm my b lmtd.Nonthle, they may rct hrd pct ofran functon common to th dffrnt clnclgroup. For xmple, Topogrphc Prol 2 wcharctrzed by covryng topogrphc ncran occiptal and parl functon octd wth dcrea n temporal lob nd mdbrn functon. B

cu of th commonlty of th prol to bothnorml nd d populton, w aocte th

prol wth th yopn rtng tt. Smlarly,the rltv hypofuncton of h mdbrn nd mdal tmporl ar my rc low ctvty of thretcular and lmbc attntonal ytm (ulm,1981) n an unfocued nontkdrvn rtng tt.

SS may alo dntfy opogrphc proflhard by dffrnt d tt. W found thtalthough PD and SND dvrg n thr rprntton of Topogrphc Prol 1 the two phnomnologcally mlr condton my hr othr topogrphc ftur indctve of bnorml motor

ytm output. n th vn, t of ntrt thtSSF valu, whch rct varyng dgr of prmotor and upplmntary moor functon, myb bnormally lvad n SND, wth trnd toward lvaton n vrtymtchd PD ptnt(Fig. 5). Th rult mut be ntrprtd wthcauton n tht thy fl to achv gncnc wththe conrvtv Bonfrron corrcton for th thrSSF compard. Nonthl, th rgonl topogrhy of th unrottd prol nurontomcllyrlvnt n that, lke Topogrphc Prol 1 t lorect ky lmnt of cortcal motor output. Thuggt that th bwngroup dffrnc n thoctd ubjct cor my not b du trctly tochanc. Wh th cvt, th ndng mly thtSND nd PD may effct thr clncl mntton through common mchnm: rducd functon of prmo tor nd SMA cortcl ffrnt rojcton. ndd, rducd ctvty n th cortcl rgon h bn uggtd th functonl b forthe kna chrctrng clncl prknonm(.g., Plyford t aI., 1992 Watt nd ndr,1992). Nonthl, SA and prmotor hypofunc


15/19


tion may be the result of abnormalities in separateneural systems in different forms of parkinsonism:in PD, with primarily nigral dysfunction and lenti-form metabolism, through an accentuation ofToporaphic Prole 1; in SND, with primarily stri-atal dysfunction and lentiform metabolism,

through an accentuation of Topographic Prole 3.

Potetial cliical applicatiosDisease Severity Assessment. We found that

SSF scores correated significantly with &Yscores and composite motor UPDRS ratings ofoverall disease severity, as well as with individualUPDRS ratings for rigidity and bradykinesia Thesignicance of these ndings must be interpreted inthe context of the mltiple correlations performedbetween each of the seven clinical measures andnumerous regional metabolic measures Because ofthe close relationship between the overal severity

ratings and the individual bradykinesia, rigidity,and gait ratings, these scores could not be consid-ered as independent observations in the clinicalmetabolic correlations which were performed Wetherefore chose to correct the signicance levels ofthese correlations for the two major independentsubsets of clinical scores within the motor UPDRS(ie, bradykinesia, rigidity, and gait scores vstremor scores) As in our earlier report (Eidelberget a, 1990), none of the clinical correlations withthe many rCMR and rCMR/GMR measuresachieved significanceeven without the Bonfer-roni correction This contrasts with the clinical

metabolic correlations of SSF I Correlations of thisparameter wit h H&Y scores, composite motorscores, and individual bradykinesia and rigidityscores were all signicant, even with a stringentcorrection for multiple regional comparisons, andwere all of a similar magnitude (R

30) These

signicant clinicalmetabolic correlations suggestthat the metabolic contribution of this abnormalbrain topography increases with advancing clinicaldisability These results also indicate that SSF val-ues correlate with quantitative clinical disabilitywith an accuracy comparable or superior to that ofstriata FDOPA uptake rate constants (Eideberg eta, 1990; Takikawa et a, 1994) Because of theclose intrasubject correlation between SSF valuesand striatal FDOPA uptake rate constants (Eidel-berg et a , 1990), SSF calculation may provide apractical, though indirect, measure of nigrostriataldysfunction applicable to certain clinical researchsituations We have demonstrated previously thatSSM techniques may be applied to individual pa-tient FDG/PET data to calculate the subject scorefo a predetermined topographic profile (Moeller

and Strother, 1991) Moreover, SSM may be ap-plied to sets of metabolic data acquired at differenttimes in the course of disease to gauge progressionand the effects of treatment Thus, calculating SSF values in PD patients studied longitudinally withFDG/PET can provide an additional independent

metabolic measure of disease progression beyondthe quantitative cinical examination ndeed, n accessible metabolic parmeter such as SF my bea potential alternative to FDOPA uptake as an im-aging marker in longitudinal studies of disease pro-gression and in assessing the effects of pharma-coprotective therapies A comprehensive comparative study will be needed to assess te relativemerits of these two PET methods as potential markers of the parkinsonian disease process

Early Diagnosis and Preclinical Detection Al-though the major topographic prole extracted fromthe analysis of bihemispheric rCM data diffe-

entiated the PD group from agemtched normals,its discriminative value is limited to PDpatients inwhom the clinical diagnosis is generaly obviousSSF was not different in the normal and PD sub-groups and did not discriminate those tients frwhom differentiation from normal is clinicly elevant Nonetheless, our data demonstrate the ten-tial applicbility of the topograpic contrst pesin discriminating the mildest patients (H Y Ste )from normals We found that the SSF scores crrectly classied all ve H&Y patients, while isclassifying only 2 of 20 normals (Fig 3 ) his ereeof discrimination is comparable to tht achieve

with FDOPA/PET (Brooks et a , 1990; kikwa eta , 1994), suggesting the applicability of F mesurements in mildly affected ptients in wm theclinical diagnosis is uncertain n contrast to the&Y patients, the more advanced patients werenot accurately discriminated fro normls by F measures Nonetheless, these patients ae enelyeasily identied clinically and ae not apt to be cnfused with normals ndeed, SSF measures fmbihemispheric rCMR analysis may be moe suitable for identifying advanced tients i ditilmetabolic data are needed to suppor the ciicdiagnosis

The topographic contrast proes deict cvying metabolic asymmetries of smal mituethat underlie the clinica motor asymmety chrcteristic of the early parkinsonian state e funthat the topographic representation of these asymmetries includes fragments of te abnol bilterproe, involving primarily the entifrm nuceus,thalamus, nd paracentra corex Aditialy, tecontrast prole that discriminte tients ithearly disease was reproducible in the i dtset

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D EIDELBERG ET AL

Tese topograpc contrast proles quantfy nher-ent metabolc asymmetres wc lke clncalasymmetres are evdent n te earlest symptom-atc stages of te llness (Hoen and Yar 1967). tappears tat relatve lentform hypermetabolsm ap-pears rst contralateral to the nvolved emparkn-

sonan lmbs pslateral to the stratum wt thegreatr degree of presynaptc ngrostratal dopam-nergic dysfuncton (Edelberg et a. 1990). As ngraldegeneraton progresses and generalzes the dopa-mnergc functonng of te opposte sde also de-creases resultng n blateral clncal nvolvementand concomtant blateral metabolc canges. Thus

wt te development of clncal parknsonsm ametabolc transton appears to occur between astate of normal symmetry and a state of patholog-cal clncal and metabolc asymmetry. Contrast pro-le descrptors suc as SSF may terefore haveutlty n delneatng ts transton. Moreove r

SSF calculaton n ndvdual cases may have cln-cal value n confrmng te dagnoss of PD nmldly affected asymmetrcal patents. Addton-ally to te etent tat te ngral cell loss s lkely tobe somewat asymmetrcal over te perod of tmeantecedng clncal symptoms SSF mght havevalue n te preclncal dentcaton of ndvdualsat rsk for PD on genetc or envronmental grounds.Terefore SSF values may provde a useful alter-natve to tradtonal FDOPA/PET methods in ths

regard (Brooks 1991; Sawle 1993 ). The realscclncal utlty of te contrast proles n early dag-noss and preclncal detecton can be ascertaned

only troug te study of more early nvolved pa-tents and preclncal coorts.

Dferential D iagnosis . t s known tat up to 25of patents clncally dagnosed n lfe with PD haveevdence of oter degeneratve dsorders at post-mortem evaluaton (Rput 1984; Gbb 1992). Al-toug tese oter condtons are patologcallyeterogeneous and some are dentable on clncalgrounds by caracterstc neurologcal sgns teyare often ndstngusable from eac oter as wellas from PD. We ave used quanttatve FDG/PETto caracterze and dfferentate some of these ds-orders (Edelberg et a. 1991, 1993; Edelberg1992; Przedborsk et a. 1993). SND represents teaknetcrgd dsorder clncally most lke PD ac-countng for 10 of the parknsonan dsorders e-amned at postmortem (Gbb 1992). Because SSManalyses are performed on combned clncal sam-ples and are blnd to patent class desgnatons wesougt to utlze ts metod to eplore ts potenalapplcaton n te dfferental dagnoss of clncallysmlar (but presumably pathologcally dfferent)neurologcal condtons. n the current nvestgation

Crb Bl Flw Mtab Vl 14 N5 1994

we used te SND populaton to address te follow-ng questons relatng to te use of SSM descrptorsn dfferental dagnoss: (a) Dd te ncluson of athrd clncally dscrete coort nto te SSM analy-ss ntroduce a new topograpc prole not evdentn the orginal twogroup analyss? (b) Dd te n-

cluson of the thrd grou alter te metabolc topog-raphy of the proles etracted from te orgnaltwogroup analyss and (c) Dd any of te SSMdescrptors dscrmnate ndvdual SND patientsfrom ther severtymatched PD counterparts wtsucent accuracy to be useful as an magng ad-junct to the clncal eamnaton?

n a

Xe perfusion study of mood dsorder pa-tents Sackem et a. (1993) demonstrated tat thencluson of a AD cohort wth a dstnctly dfferentpathology may ntroduce addtonal topograpcproles related speccally to te newly ncludeddisease type. Moreover patents n te added co-

hort had altered representations of te other topo-graphc proles. n contrast we found tat the n-cluson of SND patents n the SSM analyss dd notcreate a novel SNDspecc covarance prole Our

ndngs also ndcate that the topograpes of tethree major covarance proles were not altered bythe ncluson of SND patents. Rather SND and PDshared a common topographc space and dfferedonly n topographc prole scale and orentaton(.e. SSF magntude and sgn). As epected from

pror reports on lentform ypometabolsm n SND(DeVolder et a. 1989; Edelberg et a. 1993), temean SSF for ths group was negatve and lower

than n te PD group (Fg. 5A). We nterpret tesendngs to suggest tat SSF elevatons are ndca-tve of prmarly ngral dysfuncton (PD) wleSSF reductons reect predomnantly stratal dys-

functon (SND).We found tat n ndvdual patents SSF con-

rmed the clncal dagnoss n 9 of 10 presumedSND patents and 9 of 10 age and severtymatcedclncal PD patents. Because te clncal dfferent-aton of the parknsonan movement dsorders s n-herently mprecse oter metods of dstngusngthese patents may serve as useful adjuncts to teclncal eamnaton. Our ndngs suggest tat SSMcalculatons of SSF from ndvdual FDG/PETscans may have sucent senstvty to enhance teaccuracy of te derental dagnoss of PD andSND made solely on clncal grounds. Nonetelessthe senstivty of SSF n dscrmnatng tese cln-cally smlar conditons was only mnmaly supe-ror to tat of normalzed stratal rCMR values orF count rates (Eidelberg et a. 1993). However dfferentatons based upon PET measurements nsngle bran regons may be complcated by poten


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THE METABOLIC TOPOGRAPHY OF PARSONISM

tal observer bas and partal volume effects (Mazzoa et aI. 1981). n contrast the use of topographccovaraton profles nvolvng metabolc nformaton from multple bran regons may mnmze sucherrors. t sh uld be noted however that becausemetabolc changes are assocated wth clncal pro

gresson n both groups such dagnostc algorthmsrequre control groups strctly matched for dseaseseverty age and pharmacologc status. Furtherstudes wth longtudnal comparsons and postmortem pathologcal conrmaton are needed to ascertan the full dagnostc potental of ths technque nreaton to the clncal examnaton.

Conlusionsn ths work we demonstrate the utlty of quan

ttatve FDG/PET methods n dentfyng abnormalbran topographc proles n PD and elated dsorders. These topographc proles conform to knownanatomcal systems assocated wth locomoton andto regonal metabolc data from expermental anmals models of parnsonsm. We have also demonstrated the reproducblty of these proflesacross populatons and nstrumentaton.

Apart from ther relevance to the understandngof the metabolc organzaton of parknsonsmthese topographc profles have potental clncalapplcablty n dfferental dagnoss and obectvedsease assessment. Our results suggest further applcatons for early dagnoss and preclncal detecton. Presently dynamc FDOPA/PET methodsserve as the bestcharacterzed tools for addressng

these clncalresearch ssues (Broos et aI. 1991;Edelberg 1992; Sawle 1993). However becauseof techncal dcultes n mplementng these methods very few centers can undertake quanttatveFDOPA/PET magng on a regular bass. n contrast FDG/PET methods are techncally easer tomplement n most centers and may afford compa

rable data. Furthermore to the extent that metabolsm s coupled to perfuson n these dsorders (Otsuka et aI. 1991) analogous SSM approaches maybe applcable to regonal cerebral blood ow mappng wth other magng modaltes such as snglephoton emsson CT and functonal MR.

Acknowledent: This work was supported by grantsfrom the Parkinson Dise ase Foundation and the Dy stoniaMedical Res earch Foundation. D.E. i s a faculty fellow ofthe Parkinson D isea se Foundation and the U nited Prkinson Foundation. S.T. is a Veola T. Kerr fellow of theParkinson Disease Foundation. We thnk Dr. AbdelBelakhlef Mr. Cla ude Margouleff and Ms. Jan ie Dll forhelp with the PET studies Dr. Robert Dahl and Mr.Ralph Matacchieri for cyclotron support, and Ms DebraSegal for manuscript preparation. We are grateful to Professor Harold A Sackeim Dr. Mrtin Lesser and Dr.

Francine andel for their helpfu comments. We acknowledge Dr. David A. Rottenberg's important contribution to the earlie PET studies (Eideberg et a. 1990)and thank him for poviding those data to us for statisticalcomparison.

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