The Metabolic Anatomy of Parkinson's Disease: Complementary [ 18F]Fluorodeoxyglucoseand ['8F]Fluorodopa Positron Emission Tomographic Studies

Movement Disorders Vol. 5, No. 3, 1990, pp. 203-213 0 1990 Movement Disorder Society

*tSD. Eidelberg, "J. R. Moeller, *tSV. Dhawan, *tJ. J. Sidtis, *tJ. Z. Ginos, *tS. C. Strother, *§J. Cedarbaum, "P. Greene, /IS. Fahn, and *tD. A. Rottenberg

*Department of Neurology, Memorial Sloan-Kettering Cancer Center and fCornell University Medical College, New York, $Department of Neurology, North Shore University Hospital, Manhasset, §Department of Neurology, Burke Rehabilitation Hospital, White Plains, and IIDepartment of Neurology, Columbia University College of Physicians and Surgeons, Neurological Institute, New York, New York, U.S.A.

Summary: We studied the metabolic anatomy of typical Parkinson's disease (PD) using ['8F]fluorodeoxyglucose (FDG) and [ '*F]fluorodopa (FDOPA) and positron emission tomography (PET). Fourteen PD patients (mean age 49 years) had FDG/PET scans, of which 11 were scanned with both FDOPA and FDG. After the injection of FDOPA, brain uptake and arterial plasma radioactivity were monitored for 2 h. Striatal FDOPA uptake was analyzed with regard to a two-compartment model, and target-to-background ratios (TBRs) and TBR-versus-time slopes were also calculated. Regional patterns of metabolic covariation were extracted from FDG/PET data using the Scaled Sub- profile Model (SSM). SSM pattern weights, FDOPA uptake constants (Ki), TBRs, and TBR slopes were correlated with clinical measures for bradykinesia, rigidity, tremor, gait disturbance, left-right asymmetry, dementia, and overall disease severity. In PD patients, rate constants for FDOPA uptake correlated with individual measures of bradykinesia (p = 0.001) and gait disability (p < 0.05). SSM analysis revealed a distinct pattern of regional metabolic asymmetries, which correlated with motor asymmetries (p < 0.001) and left-right differences in Ki (p < 0.01). Our data suggest that in PD patients, FDGPET and FDOPMPET may provide unique and complementary informa- tion about underlying disease processes. Key Words: Metabolic anatomy- Parkinson's disease-['8F]Fluorodeoxyglucose-['8F]Fluorodopa-Positron emission tomography.

Although the primary biochemical lesion in Par- Address correspondence and reprint requests to Dr. D. Eidel- kinson's disease (PD) is localized to the substantia berg at Department of Neurology, North Shore University Hos- pital, Cornell University Medical College, 300 Community nkra and its dopaminergic projections (11, the ce- Drive, Manhasset, NY 11030, U.S.A. rebral metabolic consequences of nigral dopamine Dr. J. R. Moeller's present address is Department of Psychi- depletion may be widespread (2-4). T~ characterize atry , Columbia University College of Physicians and Surgeons, Psychiatric Institute, New York, NY. the metabolic consequences of PD, investigators Dr. S. C. Strother's and Dr. D. A. Rottenberg's present ad- have used positron emission tomography (PET) and dress is PET Imaging Service, Veteran's Administration Medical radiotracers directed at different metabolic cornPo- Center, One Veterans Drive, Minneapolis, MN. Dr. J. J. Sidtis's present address is Department of Neurology, nents Of the disorder. The Of PET University of Minnesota, Minneapolis, MN. studies of regional cerebral blood flow (rCBF) and

203 204 D. EIDELBERG ET AL. oxygen metabolic rate (rCMRO,) with %-labeled niques, attempts to describe the metabolic anatomy compounds have been inconsistent (5,6). Some in- of PD should ideally use complementary methods vestigators have postulated a trend toward contra- (16-18). In this study we employed FDOPNPET to lateral increases in rCBF and rCMRO, in hemipar- study the ascending nigrostriatal system, and FDG/ kinsonian patients, perhaps a reflection of pallidal PET to detect global and region-specific metabolic disinhibition (5). Studies of regional glucose metab- alterations. olism (rCMRGlc) using [18F]fluorodeoxyglucose METHODS (FDG) have not been definitive, suggesting either basal ganglia hypermetabolism (7) or global meta- Patients bolic reductions in bilaterally affected patients and We studied 14 patients [13 men and 1 woman, age in those with dementia (8). Martin et al. (9) reported 49 ? 12 years (mean -+ SD), mean disease duration glucose hypermetabolism in the contralateral palli- 9.6 years] with clinical findings consistent with PD dum in hemiparkinsonism. (Table 1). Two patients with childhood-onset PD The radiolabeled dopamine precursor ["FI- (patients 8 and 9) were included in this group. Eight fluoro-L-Dopa (FDOPA) has been used with PET to patients were treated with levodopa, of which four map the distribution of presynaptic dopaminergic also received a D, agonist (one, bromocriptine; terminals in primates (10) and in human subjects three, pergolide); two patients received bromocrip- (11-13). This technique has been useful in distin- tine and an anticholinergic agent (trihexyphenidyl), guishing normal volunteers from PD patients on the two were treated only with anticholinergic drugs, basis of striatal dopamine uptake and in correlating and two others were untreated. Magnetic resonance clinical signs with FDOPA uptake (12-15). Al- imaging and/or computed tomography scans, ob- though suitable for mapping the terminal distribu- tained in seven patients, were normal. Patients tion of the compact nigrostriatal projection, were graded using a modification of the Unified Par- FDOPNPET has not been successful in delineating kinson Disease Rating Scale (19,20). Dementia was the more diffuse dopaminergic projections to the rated on a relative &3 scale (0, absent; 1, mild; 2, mesocortex or in characterizing important meta- moderate; 3, severe). Patients were also rated on bolic alterations in remote, nondopaminoceptive, overall disease severity according to Hoehn and cortical areas. Yahr (21). Disease asymmetry, defined as the max- Because of the different types of functional infor- imal left-right difference in clinical ratings for limb mation provided by the abovementioned PET tech- rigidity and tremor, was scored from -3 to +3.

TABLE 1. Summary of study patients

~~ ~ Clinical ratingsn Patient Duration H&Y (age, yrs) (yrs) stage BK T R A D Drugsb PET studies 1 (63) 2 I1 1 1 2 2 0 1 FDG 2 (44) 3 I1 0 2 1 2 0 3 FDG/FDOPA 3 (49) 19 V 3 2 2 2 0 1,2,3 FDG/FDOPA 4 (52) 19 V 3 1 0 -1 0 1A3 FDGlFDOPA 5 (71) 3 I1 1 2 2 2 0 4 FDG 6 (45) 6 111 2 2 2 0 0 1 FDG/FDOPA 7 (53) 10 I1 3 0 2 0 0 1,3 FDG/FDOPA 8 (26) 18 V 3 2 I 0 2 2,3 FDGlFDOPA 9 (35) 28 V 3 1 3 0 1 1,2,3 FDG/FDOPA 10 (61) 6 IV 4 3 3 0 1 1 FDG/FDOPA 11 (39) 2 I 1 1 1 -1 0 4 FDGlFDOPA 12 (58) 6 I11 2 1 1 -2 0 172 FDG 13 (49) 4 I 1 3 2 -2 0 3 FDG/FDOPA 14 (44) 16 V 1 0 2 -2 2 2,3 FDGlFDOPA

H & Y, Hoehn and Yahr; BK, bradykinesia; T, tremor; R, rigidity; A, asymmetry; D, dementia; PET, positron emission tomography; FDG, ['8F]fluorodeoxyglucose;FDOPA, ['8F]fluorodopa. Clinical assessment was at the time of the FDG/PET scan when patients were taking all their medications. See text for an explanation of the clinical scores. * Medications are signified numerically: 1, levodopa; 2, D, agonists (bromocriptine or pergolide); 3, anticholinergic drugs (trihexyphenidyl); 4, untreated.

Movement Disorders, Vol. 5, No. 3, 1990 METABOLIC ANATOMY OF PARKINSON’S DISEASE 205

Positive numbers indicate predominantly right- tion for FDOPA, samples were extracted with alu- side disability, negative values predominantly left- mina as described by Boyes et al. (28). side disability; a null score indicates symmetrical Region-of-interest (ROI) analysis was performed limb involvement. In all cases, clinical disability on 128 X 128 PET reconstructions that were cor- was rated 1-2 h before FDG/PET scanning. rected for random coincidences, electronic dead time, and tissue attenuation. A single scalar correc- Normal Controls tion was used to compensate for scatter effects in Eighteen volunteer subjects with a mean age of 27 transmission, cross-calibration, and emission * 5 years, without a history of recent medical ill- scans. Rectangular ROIs were placed interactively ness, neurological disease, developmental disorder, on composite (30-120 min) PET brain slices, to en- or substance abuse, served as a control population compass the striatum; peak count rates were de- for the metabolic studies. The group consisted of 12 rived by averaging the upper 15% of pixel values. men and 6 women; all but two of the subjects were Background count rates were determined individu- right-handed. Control subjects underwent a com- ally for occipital, parietal, and cerebellar ROIs. plete neurological examination, audiometric screen- ing, and neuropsychological evaluation before FDGE’ET FDG/PET scanning. Four additional volunteer sub- Fourteen PD patients and 18 control subjects jects ages 22-34 years served as controls for the were studied with FDG and PET. Patients and con- FDOPNPET studies. trol subjects fasted overnight and were allowed a Positron Emission Tomography light breakfast 6 h before FDG/PET scanning. Pa- tients taking levodopa and other antiparkinsonian FDOPAPET drugs remained on these medications during their Eleven patients and four control subjects were neurological examination and subsequent FDG/ studied with FDOPA and PET. Patients fasted PET study. FDG, produced by a modification of overnight before FDOPNPET scanning. In 10 pa- Tewson’s synthesis (29,30), was >97% radiochem- tients, quantitative plasma amino acid analyses ically pure (specific activity 500 mCi/mmol). Serial were performed to detect the presence of endoge- PET images (10 X 1 min, 5 X 2 min, 3 x 5 min, 3 x nous large neutral amino acids that may compete 10 min) were obtained after the injection of 5-10 with FDOPA for brain uptake (22,23). In those six mCi of the tracer during a controlled resting state patients treated with levodopa, this medication was similar to that described for the FDOPA studies. discontinued at least 6 h before FDOPA/PET scan- The time course of plasma 18F radioactivity was ning to minimize interference with FDOPA uptake; determined by sampling radial arterial blood. other medications were continued. All patients re- Twenty-four (12 per hemisphere) standardized ceived 25 mg carbidopa 30 min before FDOPA was cortical and subcortical gray matter (GM) ROIs and injected. two cerebellar and two brainstem ROIs were out- FDOPA was prepared by a modification of the lined on reconstructed PET brain slices with refer- synthesis of Luxen et al. (24) and was >95% radi- ence to a neuroanatomical atlas (31). In 13 of the 14 ochemically pure (specific activity 120 mCi/mmol). PD studies, compartmental GM rate constants (kl- Serial PET images (six X 5 min, nine X 10 min) k,) and cerebral blood volumes were estimated from were obtained with the PC4600 positron camera (25) the time course of blood and regional brain radio- after an injection of 1-5 mCi of tracer. Patient and activity (32); the data from one PD study were ex- control scans were obtained in a standard resting cluded for technical reasons. To reduce intersubject state with the patient’s eyes patched and with min- variability, individual subjects’ mean rate con- imal auditory stimulation (26,27). Typical FDOPN stants, averaged across GM ROIs, were used to PET scans of a normal control and PD patient are “functionalize” raw-count images acquired be- illustrated in Fig. 1A. The time course of blood 18F tween 45 and 55 min after tracer injection (33,34). radioactivity was determined by arterial sampling. “Peak” rCMRGlc values were obtained by averag- The presence of FDOPA and 3-0-methyl FDOPA ing the upper 10% of functionalized ROI pixel val- (3-OMFD) was confirmed using high-pressure liq- ues. (The FDOPA and FDG/PET thresholds of 15 uid chromatography in two non-levodopa-treated and lo%, respectively, provided an equivalent de- patients. To define the specific arterial input func- gree of measurement stability.) Whenever anatom-

Movement Disorders, Vol. 5, No. 3, 1990 206 I). EIDELBERG ET AL.

FIG. 1. A: ['*F]Fluorodopa (FDOPA) positron emission tomographic brain slices at the level of the basal ganglia from a normal subject (RSC, left) and an age- matched patient with Parkinson's Disease (PD) (SLS, right). The color stripe quantifies I8F radioactivity at 2 h after FDOPA injection (black: 0 cpm/voxel; white: 62 cpmlvoxel). Striatal '*F uptake is decreased in the PD patient. B: Graphic analysis of FDOPA uptake 'Oi C' from 60 to 120 min postinjection for the two subjects whose scans are illustrated in (A). The ordinate represents the ratio of background-subtracted striatal 18F 5 radioactivity (A,) to plasma FDOPA concentration at time t [CJt)]. The abscissa represents the ratio of the plasma-time integral (PTI) to CP(c). At steady state ~q and in the absence of backflux, the slope of this line is *! 0 equivalent to the uptake rate constant for FDOPA and J 200 400 600 800 1000 1200 is greater for the normal subject (upper trace) than for the PD patient (lower trace). PTl/Cp(t) (min) ical regions straddled contiguous PET brain slices, Data Analysis rCMRGlc was calculated by weighting component ROI values by the number of thresholded pixels. To FDOPARET facilitate comparison with previously published Parietal, occipital, and cerebellar ROIs were se- rCMRGlc data, the lumped constant was assumed lected as background regions, and the time course to be 0.42 (34). of brain radioactivity was monitored for 2 h. In all

Movement Disorders, Vol. 5, No. 3, 1990 METABOLIC ANATOMY OF PARKINSON’S DISEASE 207 patients, target-to-background (TBR) values were scribed by a weighting factor, w. SSM pattern derived by dividing striatal count rates by average weights were correlated with clinical disability rat- background values. [Unmetabolized FDOPA, ex- ings and FDOPA uptake measurements. travesicular 6-[ ‘8F]fluorodopamine and its labeled ClinicaVPET Correlations metabolites, and 3-OMFD probably account for most of the background activity (13,35,36).] TBR A correlational analysis of clinical scores ratios for right and left striatum were calculated at (bradykinesia, rigidity, tremor, dementia, and gait each time point between 60 and 120 min after injec- disturbance), age, duration of illness, and overall tion for each of the two PET planes in which the disease severity (Hoehn and Yahr scores) was per- striata typically appear, and the plane associated formed. Pairwise correlations between individual with the larger ratio was selected. Striatal 60- clinical scores identified interrelated subsets of to 120-min TBR values were fit to a straight line by scores that were then averaged to form composite least squares to obtain the “TBR slope.” The TBR clinical scores. These composite scores, as well as at 120 min and the TBR slope were used as indices individual test scores, patient age, and duration of of dopamine uptake for subsequent data analysis. illness, were correlated with FDOPNPET results, Kinetic measures of FDOPA uptake were derived rCMRGlc values, and SSM pattern weights. graphically as described by Patlak et al. (37). For this analysis, background count rates were sub- RESULTS tracted from striatal 18F activity, and an uptake rate constant for FDOPA (KJ was derived based on the FDOPA/PET time course of brain and plasma FDOPA radioac- Quantitative amino acid analysis of plasma sam- tivity. The graphic analysis for the estimation of ples obtained from 10 patients immediately before FDOPA uptake constants is illustrated in Fig. 1B. FDOPNPET scanning did not reveal elevated lev- This analysis assumes that there is no tracer back- els of histidine, isoleucine , leucine, methionine , flux and that a steady state is achieved during the phenylalanine, tyrosine, or valine-amino acids period of study. Side-to-side differences in striatal known to compete with FDOPA for brain uptake TBR, TBR slope, and Ki were used as measures of (22,23). neurochemical asymmetry: positive values indicate The time course of “background” brain radioac- greater FDOPA uptake in the left striatum relative tivity after FDOPA injection was monitored in each to the right; negative values indicates the opposite. patient and control subject. In all cases, “F activity in the cerebellum was greater than in parietal or FDGPET occipital cortex during the first 30 min after FDOPA Absolute rCMRGlc values were obtained from injection, suggesting regional differences in amino patient and control scans for a standard set of ROIs acid transport (40) (Fig. 2). Because of the paucity in the two hemispheres. Measures of left-right con- of dopaminergic projections to the occipital lobes trast were computed as (L - R)/(L + R) x 100, (10,11,41) and because the initial uptake of 18F ra- where L and R refer to left- and right-side regional dioactivity was lowest in the occipital cortex, the values, respectively (38). Group mean regional dif- latter was chosen as the control region for all ferences were compared using Student’s f test and FDOPA/PET studies. Parameter values derived 95% confidence limits incorporating the Bonferroni from FDOPA uptake data (TBR, TBR slope, and correction for multiple comparisons. Ki) are listed in Table 2. To determine whether the pattern of metabolic Pairwise correlation between TBR at 120 min and activity of one or more subsets of brain regions dis- Ki was significant (p < 0.02), and the TBR slope tinguished PD patients from controls, patient and between 60 and 120 min was significantly correlated control rCMRGlc data sets were analyzed using the with Ki (p < 0.03). Left-right asymmetries in Ki Scaled Subprofile Model (SSM) (39). A mathemat- were highly correlated with left-right differences in ical description of SSM and its application to FDG/ TBR slope (p < 0.01), but not with absolute TBR PET patient data sets is provided elsewhere differences. (26,27,39). An SSM analysis yields one or more statistically significant patterns of regional metabolic FDGPET covariation, P; the extent to which each pattern GM rate constants were estimated regionally as contributes to a subject’s rCMRGlc profile is de- described by Anderson et al. (27). In PD patients,

Movement Disorders, Vol. 5, No. 3, 1990 208 D. EIDELBERG ET AL.

90 0-0 Cerebellum 1 A-A Parietal Ctx 111 80 X 0-0 Occipital Ctx 0 70 FIG. 2. The time course of '*F radioactivity in 3 parietal, occipital, and cerebellar "background" E:' 60 regions after ['8F]fluorodopainjection (patient 8, a Table 1). During the first 60 min postinjection, 0 50 the uptake of "F radioactivity is greatest in the 40 cerebellum and least in the occipital cortex; between 60 and 120 min, these regional differences 30 are no longer apparent. 20

10 0 12 24 36 48 60 72 04 96 168 1 0 Time in Minutes estimated values for k, (mean 0.063) were signifi- subjects, mean left-right rCMRGlc contrast did not cantly lower than control values (mean 0.084, p C exceed 5%; likewise, in PD patients, regional left- 0.001), whereas estimates of k, and k, were not dif- right rCMRGlc differences did not differ from nor- ferent from control values. Mean rCMRGlc values mal values. for basal ganglia, thalamus, and all cortical ROIs SSM analysis was performed on the combined except the hippocampus (ROI 30, Fig. 3) were sig- group of PD patients and normal volunteers nificantly lower (p < 0.03) for PD patients relative (26,27,39). The subject weights, W,, for the signif- to mean control values. For PD patients and normal icant metabolic covariance pattern, PI, were highly correlated with Ki (p < 0.02), but not with TBR. TABLE 2. Fluorodopa scan quantitation SSM analysis of left-right differences in rCMRGlc revealed a covariance pattern of regional asymme- PD Patients TBR" TBR slopeb K; tries, P,, with its subject-specific weighting factors, W,. P2 was largely determined by metabolic asym- Patient Left Right Left Right Left Right

~ metries in the basal ganglia, thalamus, and poste- 2 2.20 2.56 1.08 1.66 8.27 13.40 rior temporal cortex (Fig. 4). Positive W, values 3 1.87 2.20 0.65 0.84 4.38 5.12 4 1.46 1.46 0.24 0.12 2.17 1.99 indicate relative increases in left hemispheric 6 2.48 2.15 1.23 0.88 - - rCMRGlc, but negative W, values indicate the op- 1 1.55 1.66 0.68 0.73 5.92 6.66 posite. There was a significant negative correlation 8 1.75 1.70 0.60 0.58 3.42 3.11 9 2.03 1.94 0.25 0.22 5.55 4.94 between W, values and left-right differences in Ki 10 1.92 1.90 0.47 0.60 4.39 4.50 (p < 0.01), such that decreases in striatal FDOPA 11 2.25 2.09 0.55 0.49 7.81 6.27 uptake were associated with relative increases in 13 1.85 2.07 0.79 0.80 8.93 8.08 14 2.67 2.47 1.27 0.89 10.20 7.16 the regional glucose metabolism in the ipsilateral hemisphere. Both the P, and P, patterns were Control subjects Subject TBR TBR slope K, statistically significant and each accounted for >50% of the Subject Residual Profile variance (39) 1 2.81 2.84 1.05 1.22 17.79 20.06 2 2.62 2.42 1.63 1.21 12.35 9.55 determined in the respective SSM analyses. 3 2.40 2.91 1.12 1.76 - - 4 2.66 2.83 1.07 1.55 - - ClinicalPET Correlations a TBR refers to striata1:occipitaltarget-to-background ratio 2 h after [18F]fluorodopa(FDOPA) injection. Left and right values refer to the left and right striatum, respectively. All FDOPAIPET indices of dopaminergic func- TBR slope refers to the slope of a straight line fitted to stri- tion (TBR, TBR slope, Ki) measured in PD patients atal TBRs calculated at 60,70, 80,90, 100, 110, and 120 min after were lower than normal (but not age-matched) con- FDOPA injection. Kirefers to the calculated striatal uptake rate constant for trol values. Ki was highly correlated with individual FDOPA (min-' x measures of bradykinesia (p = 0.001) and gait dis-

Movement Disorders, Vol. 5, No. 3, 1990 METABOLIC ANATOMY OF PARKINSON'S DISEASE 209

89$ FIG. 3. Mean regional cerebral metabolic rate for glucose (rCMRGlc) values for 13 patients with Parkinson's disease and 18 normal control subjects. rCMRGlc values are plotted as a function of region-of-interest (ROI) number (no.) and hemisphere to produce metabolic profiles. Left and right hemisphere values are plotted as ROI no. and (no. + I), respectively. Error bars footed on the control profile represent the 95% confi- 4 dence intervals for the difference between regional means. ROI code: 5, cerebellum; 10, brainstem; 15, midbrain; 20, 3 basal ganglia; 25, thalamus; 30, hippocampus; 35, lateral temporal cortex; 40, opercular cortex; 45, posterior temporal 2 cortex; 50, medial frontal cortex; 55, lateral frontal cortex; 60, calcarine cortex; 65, cuneus; 70, inferior parietal cortex; 1 I 75, paracentral cortex. Ie 5 ie 15 28 25 38 35 4e 45 5e 55 ROI Number ability (p < 0.05) (Fig. 5). Correlation analysis of findings indicate a decrease in striatal FDOPA up- PD clinical scores revealed a strong pairwise corre- take and a region-specific increase in metabolism in lation (p < 0.0001) between scores for bradykinesia, the thalamus and basal ganglia contralateral to the gait disturbance, overall disease severity (Hoehn more severely affected limbs. and Yahr scores), and disease duration. An average of these scores was highly correlated with Ki values DISCUSSION (p < 0.01). Clinical correlations with TBR were not significant. There was no significant interrelation- Our results indicate that FDOPA and FDG/PET ship between the clinical scores for tremor, rigidity, studies in PD are complementary and that these and dementia, nor were there significant correla- techniques together can provide important informa- tions between these scores and FDOPNPET mea- tion regarding the metabolic substrates of this ill- surements. Ki values for patients receiving levodo- ness. FDOPMPET may be used to quantify the pri- pa (n = 6) were generally lower than Ki values for mary neurochemical lesion in PD but cannot char- nonreceivers (n = 5, p < 0.001). Clinical asymme- acterize signs and symptoms not directly related to try in PD patients was negatively correlated with dopamine depletion. FDGPET provides unique in- side-to-side differences in Ki (p < 0.01) (Fig. 6A) and formation regarding the topography of metabolic TBR (p < 0.01). changes in the brains of PD patients, which is un- Correlations between regional glucose metabolic available from studies with dopamine uptake mark- rate (rCMRGlc or rCMRGlc normalized by the ers or D2 ligands. global metabolic rate) and clinical measures were Bradykinesia scores correlated closely with mea- not significant. However, SSM-derived W1 pattern sures of FDOPA uptake. This finding is consistent weights were positively correlated with bradykine- with neurochemical studies of postmortem speci- sia scores (p < 0.02) and with age (p < 0.01). W, mens of human striatum, in which bradykinesia was pattern weights were positively correlated with clin- found to be the symptom most closely related to ical asymmetry scores (p < 0.001) (Fig. 6B). These reduced striatal dopamine content (1). Similarly, in

Movement Disorders, Vol. 5. No. 3, 1990 210 D. EIDELBERG ET AL.

ASYMMETRIC SUBPROFILE

111111111111111 0.5 111111111111111

0.0

-0.5

-1.0 4. FIG. The relative weights of 28 re- -w gions of interest (ROI’s) for the covari- -1.5 ance pattern of regional cerebral meta- D bolic rate for glucose (rCMRGlc) -d asymmetries, P,. ROI numbers are de- aJ -2.0 fined in the legend to Fig. 3. Note that 3 this pattern largely reflects covarying -2.5 metabolic asymmetries in the basal C ganglia (region 20), thalamus (region L 25) and posterior temporal cortex (re- (Ir -3.0 gion 45). The contribution of the P, pat- -w tern to each patient’s overall right-left -w -3.5 rCMRGlc contrast is represented by a u subject weighting factor, W,. a -4.0

-4.5

-5.0

-5.5 05 10 15 29 25 30 35 40 45 58 55 69 65 79 75 OM ROI Number animal models of parkinsonism, nigral lesions are pattern of motor disability in PD patients. More- most consistently associated with bradykinesia over, the finding of significant correlations between (42). The demonstration of a strong intercorrelation these clinical parameters and PET indices of striatal between bradykinesia, gait disturbance, and overall FDOPA uptake may suggest a common neurochem- disease severity points to the presence of a discrete ical basis for this subset of parkinsonian manifesta- tions. The lack of an association between FDOPN PET or FDG/PET indices and clinical ratings of rigidity, tremor, and dementia-and the absence of 10-k statistically significant correlations between these ratings-may indicate that these other disease man- 8- ifestations have different pathophysiological mechanisms and neurochemical substrates (4345). 6- Although Kivalues for PD patients were lower than for normal controls, the significance of this 4- finding remains unclear in view of the recently dem-

2- onstrated decline in Kiwith normal aging (46). Our observation of a correlation between bradykinesia

Ol I I I scores and patient subject weights (W,) for the P, 0 1 2 3 4 5 pattern of rCMRGlc covariation may be con- Bradykinesia Score founded by the effects of aging in the PD popula- FIG. 5. Clinical/positron emission tomography correlations. tion, because W, pattern weights were also highly Bradykinesia scores for Parkinson’s disease patients correlate with striatal uptake rate constants for [18F]fluorodopa(Ki) (r = correlated with age; thus, the P, pattern may not be -0.87, p = 0.001). disease specific. The finding of reduced k, and mean

Movement Disorders, Vol. 5, No. 3, 1990 METABOLIC ANATOMY OF PARKINSON’S DISEASE 211

of left-right asymmetries in PD patients reveals a distinct metabolic covariance pattern, P,, which in- cludes the basal ganglia and thalamus. The subject weights for this assymmetry pattern are highly correlated with independent measures of clinical asymmetry and left-right differences in FDOPA uptake. In 12 of our 14 PD patients, the contribution of this pattern to basal ganglia and thalamic rCMRGlc is greatest on the side opposite the more severely affected limbs, i.e., relative contralateral hypermetabolism. Our finding of relative increases in con- -6 I I I I tralateral thalamic and basal ganglia mei abolism in -3 -2 -1 0 1 2 3 Clinical Asymmetly Score asymmetric PD patients is consistent vith the no- tion of ‘‘metabolic release” of certain subcortical B 31 structures after nigral dopamine depletion. Previous PET studies of hemiparkinsonism have yielded mixed results with regard to metabolic asymmetries. Wolfson and colleagues (5) demon- 1 ,, strated a 10% coupled increase in rCBF and / rCMRO, in the basal ganglia contralateral to the affected limbs in hemiparkisonian patients. Perl- mutter and Raichle (6) described an abnormal asymmetry of pallidal blood flow in four hemiparkin-

-2y ~ sonian patients, but with relatively decreased contralateral pallidal rCBF in three. Martin et al. (9), -34-2 -1 0 1 2 3 using FDG/PET, described contralateral glucose -3 hypermetabolism in two of four hemiparkinsonian Clinical Asymmetry Score patients, although the pallidal localization of the hy- FIG. 6. Clinicallpositron emission tomography correlations. A: permetabolic focus was not demonstrated with cer- clinical asymmetry scores related to left-right differences in striatal [‘8F]fluorodopa (FDOPA) uptake rate constants (Ki): posi- tainty. tive clinical asymmetry scores correspond to predominantly In chronic PD patients, increases in basal ganglia right-side motor disability, and positive Kidifferences indicate metabolism after nigral dopamine loss may be of relative reductions in right striatal FDOPA uptake; negative values reflect the predominantly left-side motor disability and re- small magnitude and obscured by the heterogeneity duced left striatal FDOPA uptake. There is a significant negative of structure and function within a typical basal gan- correlation between clinical asymmetry scores and left-right dif- glionic ROI. Penney and Young (45) argued that ferences in Ki (r = -0.80, p = 0.00.5), indicating decreased FDOPA uptake contralateral to the more severely affected major structural and functional inhomogeneities oc- limbs. B: Clinical asymmetry scores related to W, pattern cur with the human striatum and that dopamine de- weights for metabolic asymmetry: positive W, values indicate ficiency may give rise to excitation or inhibition of regional increases in left hemispheric metabolism relative to the right; negative W, values indicate the opposite. A positive cor- differing neuronal subpopulations. This structural relation (r = 0.82, p = 0.0003) between clinical asymmetry and functional heterogeneity, which is particularly scores and W, was noted, indicating relative increases in basal marked within the globus pallidus (44,45), may ac- ganglia and thalamic glucose metabolism contralateral to the more affected limbs. count for the inconsistent results of the previous PET studies. Because of their small magnitude, rCMRGlc asymmetries in PD patients may not be rCMRGlc in PD patients is consistent with the re- demonstrable by simple left-right comparisons sults of previous FDGPET studies of parkinsonism (i.e., analysis of variance statistics). However, (8), and is unlikely to be strictly an aging effect when left-right differences in the metabolic activity (47,48). of basal ganglia subnuclei are linked to functional The metabolic landscape of PD is best described asymmetries in other brain regions, statistical tech- by an analysis of regional patterns of hemispheric niques, such as SSM, can identify these patterns of asymmetry. The application of SSM to the analysis regional covariation. By specifically restricting the

Movement Disorders, Vol. 5, No. 3, 1990 212 D. EIDELBERG ET AL.

search to regional patterns of hemispheric asymme- was supported in part by National Institutes of Health try, a small biological signal correlated with clinical grant NS-23473. and neurochemical asymmetries was extracted. REFERENCES Because clinical ratings and FDGiPET scans 1. Bernheimer H, Birkmayer W, Hornykiewicz 0, Jellinger K, were performed on one occasion, and FDOPA/PET Seitelberger F. Brain dopamine and the syndromes of Par- scans were performed on a separate occasion, the kinson and Huntington: clinical, morphological and neuro- comparability of data derived from the two PET chemical correlations. J Neurol Sci 1973;20:415455. 2. Wooten GF, Collins RC. Metabolic effects of unilateral le- studies (and their clinical correlates) might be ques- sions of the substantia nigra. J Neurosci 1981;1:285-291. tioned. In non-levodopa-treated patients, the re- 3. Porrino LJ, Burns RS, Crane AM, et al. 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