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

The Metabolic Anatomy of Parkinson's Disease: Complementary [18F]Fluorodeoxyglucoseand ['8F]Fluorodopa Positron Emission Tomographic Studies *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 Subprofile 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 information about underlying disease processes. Key Words: Metabolic anatomyParkinson's disease-['8F]Fluorodeoxyglucose-['8F]Fluorodopa-Positron emission tomography.

Although the primary biochemical lesion in Parkinson's disease (PD) is localized to the substantia nkra and its dopaminergic projections (11, the cerebral metabolic consequences of nigral dopamine depletion may be widespread (2-4). T~ characterize the metabolic consequences of PD, investigators have used positron emission tomography (PET) and radiotracers directed at different metabolic cornPonents Of the disorder. The Of PET studies of regional cerebral blood flow (rCBF) and

Address correspondence and reprint requests to Dr. D. Eidelberg at Department of Neurology, North Shore University Hospital, Cornell University Medical College, 300 Community Drive, Manhasset, NY 11030, U.S.A. Dr. J. R. Moeller's present address is Department of Psychiatry , Columbia University College of Physicians and Surgeons, Psychiatric Institute, New York, NY. Dr. S. C. Strother's and Dr. D. A. Rottenberg's present address is PET Imaging Service, Veteran's Administration Medical Center, One Veterans Drive, Minneapolis, MN. Dr. J. J. Sidtis's present address is Department of Neurology, University of Minnesota, Minneapolis, MN.

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oxygen metabolic rate (rCMRO,) with %-labeled compounds have been inconsistent (5,6). Some investigators have postulated a trend toward contralateral increases in rCBF and rCMRO, in hemiparkinsonian patients, perhaps a reflection of pallidal disinhibition (5). Studies of regional glucose metabolism (rCMRGlc) using [18F]fluorodeoxyglucose (FDG) have not been definitive, suggesting either basal ganglia hypermetabolism (7) or global metabolic reductions in bilaterally affected patients and in those with dementia (8). Martin et al. (9) reported glucose hypermetabolism in the contralateral pallidum in hemiparkinsonism. The radiolabeled dopamine precursor ["FIfluoro-L-Dopa (FDOPA) has been used with PET to map the distribution of presynaptic dopaminergic terminals in primates (10) and in human subjects (11-13). This technique has been useful in distinguishing normal volunteers from PD patients on the basis of striatal dopamine uptake and in correlating clinical signs with FDOPA uptake (12-15). Although suitable for mapping the terminal distribution of the compact nigrostriatal projection, FDOPNPET has not been successful in delineating the more diffuse dopaminergic projections to the mesocortex or in characterizing important metabolic alterations in remote, nondopaminoceptive, cortical areas. Because of the different types of functional information provided by the abovementioned PET tech-

niques, attempts to describe the metabolic anatomy of PD should ideally use complementary methods (16-18). In this study we employed FDOPNPET to study the ascending nigrostriatal system, and FDG/ PET to detect global and region-specific metabolic alterations. METHODS Patients We studied 14 patients [13 men and 1 woman, age 49 ? 12 years (mean -+ SD), mean disease duration 9.6 years] with clinical findings consistent with PD (Table 1). Two patients with childhood-onset PD (patients 8 and 9) were included in this group. Eight patients were treated with levodopa, of which four also received a D, agonist (one, bromocriptine; three, pergolide); two patients received bromocriptine and an anticholinergic agent (trihexyphenidyl), two were treated only with anticholinergic drugs, and two others were untreated. Magnetic resonance imaging and/or computed tomography scans, obtained in seven patients, were normal. Patients were graded using a modification of the Unified Parkinson Disease Rating Scale (19,20). Dementia was rated on a relative &3 scale (0, absent; 1, mild; 2, moderate; 3, severe). Patients were also rated on overall disease severity according to Hoehn and Yahr (21). Disease asymmetry, defined as the maximal left-right difference in clinical ratings for limb rigidity and tremor, was scored from - 3 to + 3 .

TABLE 1. Summary of study patients ~~

~

Patient (age, yrs)

Duration (yrs)

H&Y stage

1 (63) 2 (44) 3 (49) 4 (52) 5 (71) 6 (45) 7 (53) 8 (26) 9 (35) 10 (61) 11 (39) 12 (58) 13 (49) 14 (44)

2 3 19 19 3 6 10 18 28 6 2 6 4 16

I1 I1 V V I1 111

I1 V V IV I

I11 I V

Clinical ratingsn BK

T

R

A

D

Drugsb

PET studies

1 0 3 3 1 2 3 3 3 4 1 2 1 1

1 2 2 1 2 2 0 2 1 3 1 1 3 0

2 1 2 0 2

2 2 2 -1 2 0 0 0 0 0 -1 -2 -2 -2

0 0 0 0 0 0 0 2 1 1 0 0 0 2

1 3 1,2,3 1A 3 4 1 1,3 2,3 1,2,3 1 4 172 3 2,3

FDG FDG/FDOPA FDG/FDOPA FDGlFDOPA FDG FDG/FDOPA FDG/FDOPA FDGlFDOPA FDG/FDOPA FDG/FDOPA FDGlFDOPA FDG FDG/FDOPA FDGlFDOPA

2 2

I 3 3 1 1 2 2

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 Positive numbers indicate predominantly rightside disability, negative values predominantly leftside disability; a null score indicates symmetrical limb involvement. In all cases, clinical disability was rated 1-2 h before FDG/PET scanning. Normal Controls Eighteen volunteer subjects with a mean age of 27 5 years, without a history of recent medical illness, neurological disease, developmental disorder, or substance abuse, served as a control population for the metabolic studies. The group consisted of 12 men and 6 women; all but two of the subjects were right-handed. Control subjects underwent a complete neurological examination, audiometric screening, and neuropsychological evaluation before FDG/PET scanning. Four additional volunteer subjects ages 22-34 years served as controls for the FDOPNPET studies.

*

Positron Emission Tomography FDOPAPET Eleven patients and four control subjects were studied with FDOPA and PET. Patients fasted overnight before FDOPNPET scanning. In 10 patients, quantitative plasma amino acid analyses were performed to detect the presence of endogenous large neutral amino acids that may compete with FDOPA for brain uptake (22,23). In those six patients treated with levodopa, this medication was discontinued at least 6 h before FDOPA/PET scanning to minimize interference with FDOPA uptake; other medications were continued. All patients received 25 mg carbidopa 30 min before FDOPA was injected. FDOPA was prepared by a modification of the synthesis of Luxen et al. (24) and was >95% radiochemically pure (specific activity 120 mCi/mmol). Serial PET images (six X 5 min, nine X 10 min) were obtained with the PC4600 positron camera (25) after an injection of 1-5 mCi of tracer. Patient and control scans were obtained in a standard resting state with the patient’s eyes patched and with minimal auditory stimulation (26,27). Typical FDOPN PET scans of a normal control and PD patient are illustrated in Fig. 1A. The time course of blood 18F radioactivity was determined by arterial sampling. The presence of FDOPA and 3-0-methyl FDOPA (3-OMFD) was confirmed using high-pressure liquid chromatography in two non-levodopa-treated patients. To define the specific arterial input func-

205

tion for FDOPA, samples were extracted with alumina as described by Boyes et al. (28). Region-of-interest (ROI) analysis was performed on 128 X 128 PET reconstructions that were corrected for random coincidences, electronic dead time, and tissue attenuation. A single scalar correction was used to compensate for scatter effects in transmission, cross-calibration, and emission scans. Rectangular ROIs were placed interactively on composite (30-120 min) PET brain slices, to encompass the striatum; peak count rates were derived by averaging the upper 15% of pixel values. Background count rates were determined individually for occipital, parietal, and cerebellar ROIs. FDGE’ET Fourteen PD patients and 18 control subjects were studied with FDG and PET. Patients and control subjects fasted overnight and were allowed a light breakfast 6 h before FDG/PET scanning. Patients taking levodopa and other antiparkinsonian drugs remained on these medications during their neurological examination and subsequent FDG/ PET study. FDG, produced by a modification of Tewson’s synthesis (29,30), was >97% radiochemically pure (specific activity 500 mCi/mmol). Serial PET images (10 X 1 min, 5 X 2 min, 3 x 5 min, 3 x 10 min) were obtained after the injection of 5-10 mCi of the tracer during a controlled resting state similar to that described for the FDOPA studies. The time course of plasma 18F radioactivity was determined by sampling radial arterial blood. Twenty-four (12 per hemisphere) standardized cortical and subcortical gray matter (GM) ROIs and two cerebellar and two brainstem ROIs were outlined on reconstructed PET brain slices with reference to a neuroanatomical atlas (31). In 13 of the 14 PD studies, compartmental GM rate constants (klk,) and cerebral blood volumes were estimated from the time course of blood and regional brain radioactivity (32); the data from one PD study were excluded for technical reasons. To reduce intersubject variability, individual subjects’ mean rate constants, averaged across GM ROIs, were used to “functionalize” raw-count images acquired between 45 and 55 min after tracer injection (33,34). “Peak” rCMRGlc values were obtained by averaging the upper 10% of functionalized ROI pixel values. (The FDOPA and FDG/PET thresholds of 15 and lo%, respectively, provided an equivalent degree of measurement stability.) Whenever anatom-

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A

~q C'

'Oi

5

*!

0

J

200

600

400

800

1000

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 agematched 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 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 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 and in the absence of backflux, the slope of this line is equivalent to the uptake rate constant for FDOPA and 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, rCMRGlc was calculated by weighting component ROI values by the number of thresholded pixels. To facilitate comparison with previously published rCMRGlc data, the lumped constant was assumed to be 0.42 (34).

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Data Analysis FDOPARET Parietal, occipital, and cerebellar ROIs were selected as background regions, and the time course of brain radioactivity was monitored for 2 h. In all

METABOLIC ANATOMY OF PARKINSON’S DISEASE patients, target-to-background (TBR) values were derived by dividing striatal count rates by average background values. [Unmetabolized FDOPA, extravesicular 6-[‘8F]fluorodopamine and its labeled metabolites, and 3-OMFD probably account for most of the background activity (13,35,36).] TBR ratios for right and left striatum were calculated at each time point between 60 and 120 min after injection for each of the two PET planes in which the striata typically appear, and the plane associated with the larger ratio was selected. Striatal 60to 120-min TBR values were fit to a straight line by least squares to obtain the “TBR slope.” The TBR at 120 min and the TBR slope were used as indices of dopamine uptake for subsequent data analysis. Kinetic measures of FDOPA uptake were derived graphically as described by Patlak et al. (37). For this analysis, background count rates were subtracted from striatal 18Factivity, and an uptake rate constant for FDOPA ( K J was derived based on the time course of brain and plasma FDOPA radioactivity. The graphic analysis for the estimation of FDOPA uptake constants is illustrated in Fig. 1B. This analysis assumes that there is no tracer backflux and that a steady state is achieved during the period of study. Side-to-side differences in striatal TBR, TBR slope, and Ki were used as measures of neurochemical asymmetry: positive values indicate greater FDOPA uptake in the left striatum relative to the right; negative values indicates the opposite. FDGPET Absolute rCMRGlc values were obtained from patient and control scans for a standard set of ROIs in the two hemispheres. Measures of left-right contrast were computed as (L - R)/(L + R) x 100, where L and R refer to left- and right-side regional values, respectively (38). Group mean regional differences were compared using Student’s f test and 95% confidence limits incorporating the Bonferroni correction for multiple comparisons. To determine whether the pattern of metabolic activity of one or more subsets of brain regions distinguished PD patients from controls, patient and control rCMRGlc data sets were analyzed using the Scaled Subprofile Model (SSM) (39). A mathematical description of SSM and its application to FDG/ PET patient data sets is provided elsewhere (26,27,39). An SSM analysis yields one or more statistically significant patterns of regional metabolic covariation, P; the extent to which each pattern contributes to a subject’s rCMRGlc profile is de-

207

scribed by a weighting factor, w. SSM pattern weights were correlated with clinical disability ratings and FDOPA uptake measurements. ClinicaVPET Correlations A correlational analysis of clinical scores (bradykinesia, rigidity, tremor, dementia, and gait disturbance), age, duration of illness, and overall disease severity (Hoehn and Yahr scores) was performed. Pairwise correlations between individual clinical scores identified interrelated subsets of scores that were then averaged to form composite clinical scores. These composite scores, as well as individual test scores, patient age, and duration of illness, were correlated with FDOPNPET results, rCMRGlc values, and SSM pattern weights. RESULTS FDOPA/PET Quantitative amino acid analysis of plasma samples obtained from 10 patients immediately before FDOPNPET scanning did not reveal elevated levels of histidine, isoleucine , leucine, methionine , phenylalanine, tyrosine, or valine-amino acids known to compete with FDOPA for brain uptake (22,23). The time course of “background” brain radioactivity after FDOPA injection was monitored in each patient and control subject. In all cases, “F activity in the cerebellum was greater than in parietal or occipital cortex during the first 30 min after FDOPA injection, suggesting regional differences in amino acid transport (40) (Fig. 2). Because of the paucity of dopaminergic projections to the occipital lobes (10,11,41) and because the initial uptake of 18Fradioactivity was lowest in the occipital cortex, the latter was chosen as the control region for all FDOPA/PET studies. Parameter values derived from FDOPA uptake data (TBR, TBR slope, and K i ) are listed in Table 2. Pairwise correlation between TBR at 120 min and Ki was significant (p < 0.02), and the TBR slope between 60 and 120 min was significantly correlated with Ki (p < 0.03). Left-right asymmetries in Ki were highly correlated with left-right differences in TBR slope (p < 0.01), but not with absolute TBR differences. FDGPET GM rate constants were estimated regionally as described by Anderson et al. (27). In PD patients,

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90

1

111 X

70

E:

60

'

Cerebellum

A-A

Parietal C t x Occipital C t x

0-0

0

3

FIG. 2. The time course of '*F radioactivity in parietal, occipital, and cerebellar "background" regions after ['8F]fluorodopainjection (patient 8, Table 1). During the first 60 min postinjection, the uptake of "F radioactivity is greatest in the cerebellum and least in the occipital cortex; between 60 and 120 min, these regional differences are no longer apparent.

80

0-0

a

0

50 40

30 20

10 0

12

24

36

48

Time

estimated values for k , (mean 0.063) were significantly lower than control values (mean 0.084, p C 0.001), whereas estimates of k, and k, were not different from control values. Mean rCMRGlc values for basal ganglia, thalamus, and all cortical ROIs except the hippocampus (ROI 30, Fig. 3) were significantly lower (p < 0.03) for PD patients relative to mean control values. For PD patients and normal TABLE 2. Fluorodopa scan quantitation PD Patients TBR" Patient

TBR slopeb

K;

Left

Right

Left

Right

Left

Right

2.20 1.87 1.46 2.48 1.55 1.75 2.03 1.92 2.25 1.85 2.67

2.56 2.20 1.46 2.15 1.66 1.70 1.94 1.90 2.09 2.07 2.47

1.08 0.65 0.24 1.23 0.68 0.60 0.25 0.47 0.55 0.79 1.27

1.66 0.84 0.12 0.88 0.73 0.58 0.22 0.60 0.49 0.80 0.89

8.27 4.38 2.17 5.92 3.42 5.55 4.39 7.81 8.93 10.20

13.40 5.12 1.99

TBR slope 1.22 1.05 1.63 1.21 1.76 1.12 1.55 1.07

17.79 12.35

~

2 3 4 6 1

8 9 10

11 13 14

Control subjects Subject TBR 1 2.81 2.84 2 2.62 2.42 3 2.40 2.91 4 2.66 2.83

-

6.66 3.11 4.94 4.50 6.27 8.08 7.16

K,

-

20.06 9.55

-

TBR refers to striata1:occipitaltarget-to-backgroundratio 2 h after [18F]fluorodopa(FDOPA) injection. Left and right values refer to the left and right striatum, respectively. TBR slope refers to the slope of a straight line fitted to striatal TBRs calculated at 60,70, 80,90, 100, 110, and 120 min after FDOPA injection. Kirefers to the calculated striatal uptake rate constant for FDOPA (min-' x

60

72

04

96

168

1 0

in Minutes

subjects, mean left-right rCMRGlc contrast did not exceed 5%; likewise, in PD patients, regional leftright rCMRGlc differences did not differ from normal values. SSM analysis was performed on the combined group of PD patients and normal volunteers (26,27,39). The subject weights, W,, for the significant metabolic covariance pattern, PI, were highly correlated with Ki (p < 0.02), but not with TBR. SSM analysis of left-right differences in rCMRGlc revealed a covariance pattern of regional asymmetries, P,, with its subject-specific weighting factors, W,. P2 was largely determined by metabolic asymmetries in the basal ganglia, thalamus, and posterior temporal cortex (Fig. 4). Positive W, values indicate relative increases in left hemispheric rCMRGlc, but negative W, values indicate the opposite. There was a significant negative correlation between W, values and left-right differences in Ki (p < 0.01), such that decreases in striatal FDOPA uptake were associated with relative increases in the regional glucose metabolism in the ipsilateral hemisphere. Both the P, and P, patterns were statistically significant and each accounted for >50% of the Subject Residual Profile variance (39) determined in the respective SSM analyses. ClinicalPET Correlations

a

Movement Disorders, Vol. 5, No. 3, 1990

All FDOPAIPET indices of dopaminergic function (TBR, TBR slope, Ki) measured in PD patients were lower than normal (but not age-matched) control values. Ki was highly correlated with individual measures of bradykinesia (p = 0.001) and gait dis-

METABOLIC ANATOMY OF PARKINSON'S DISEASE

I

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% confidence intervals for the difference between regional means. ROI code: 5, cerebellum; 10, brainstem; 15, midbrain; 20, basal ganglia; 25, thalamus; 30, hippocampus; 35, lateral temporal cortex; 40, opercular cortex; 45, posterior temporal cortex; 50, medial frontal cortex; 55, lateral frontal cortex; 60, calcarine cortex; 65, cuneus; 70, inferior parietal cortex; 75, paracentral cortex.

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R O I Number ability (p < 0.05) (Fig. 5). Correlation analysis of PD clinical scores revealed a strong pairwise correlation (p < 0.0001) between scores for bradykinesia, gait disturbance, overall disease severity (Hoehn and Yahr scores), and disease duration. An average of these scores was highly correlated with Ki values (p < 0.01). Clinical correlations with TBR were not significant. There was no significant interrelationship between the clinical scores for tremor, rigidity, and dementia, nor were there significant correlations between these scores and FDOPNPET measurements. Ki values for patients receiving levodopa (n = 6) were generally lower than Ki values for nonreceivers (n = 5 , p < 0.001). Clinical asymmetry in PD patients was negatively correlated with side-to-side differences in Ki (p < 0.01) (Fig. 6A) and TBR (p < 0.01). Correlations between regional glucose metabolic rate (rCMRGlc or rCMRGlc normalized by the global metabolic rate) and clinical measures were not significant. However, SSM-derived W1 pattern weights were positively correlated with bradykinesia scores (p < 0.02) and with age (p < 0.01). W, pattern weights were positively correlated with clinical asymmetry scores (p < 0.001) (Fig. 6B). These

findings indicate a decrease in striatal FDOPA uptake and a region-specific increase in metabolism in the thalamus and basal ganglia contralateral to the more severely affected limbs. DISCUSSION Our results indicate that FDOPA and FDG/PET studies in PD are complementary and that these techniques together can provide important information regarding the metabolic substrates of this illness. FDOPMPET may be used to quantify the primary neurochemical lesion in PD but cannot characterize signs and symptoms not directly related to dopamine depletion. FDGPET provides unique information regarding the topography of metabolic changes in the brains of PD patients, which is unavailable from studies with dopamine uptake markers or D2 ligands. Bradykinesia scores correlated closely with measures of FDOPA uptake. This finding is consistent with neurochemical studies of postmortem specimens of human striatum, in which bradykinesia was found to be the symptom most closely related to reduced striatal dopamine content (1). Similarly, in

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ASYMMETRIC SUBPROFILE 0.5

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

5

10

15

29

25

30

35

40

45

58

55

69

65

79

75

0.0 -0.5 -1.0

FIG. 4. The relative weights of 28 regions of interest (ROI’s) for the covariance pattern of regional cerebral metabolic rate for glucose (rCMRGlc) asymmetries, P,. ROI numbers are defined in the legend to Fig. 3. Note that this pattern largely reflects covarying metabolic asymmetries in the basal ganglia (region 20), thalamus (region 25) and posterior temporal cortex (region 45). The contribution of the P, pattern to each patient’s overall right-left rCMRGlc contrast is represented by a subject weighting factor, W,.

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R O I Number animal models of parkinsonism, nigral lesions are most consistently associated with bradykinesia (42). The demonstration of a strong intercorrelation between bradykinesia, gait disturbance, and overall disease severity points to the presence of a discrete

-k

10

8642-

O l 0

I

I

I

1

2

3

4

5

Bradykinesia Score

FIG. 5. Clinical/positron emission tomography correlations. Bradykinesia scores for Parkinson’s disease patients correlate with striatal uptake rate constants for [18F]fluorodopa(Ki) (r = -0.87, p = 0.001).

Movement Disorders, Vol. 5 , No. 3, 1990

pattern of motor disability in PD patients. Moreover, the finding of significant correlations between these clinical parameters and PET indices of striatal FDOPA uptake may suggest a common neurochemical basis for this subset of parkinsonian manifestations. The lack of an association between FDOPN PET or FDG/PET indices and clinical ratings of rigidity, tremor, and dementia-and the absence of statistically significant correlations between these ratings-may indicate that these other disease manifestations have different pathophysiological mechanisms and neurochemical substrates (4345). Although Kivalues for PD patients were lower than for normal controls, the significance of this finding remains unclear in view of the recently demonstrated decline in Kiwith normal aging (46). Our observation of a correlation between bradykinesia scores and patient subject weights (W,) for the P, pattern of rCMRGlc covariation may be confounded by the effects of aging in the PD population, because W, pattern weights were also highly correlated with age; thus, the P, pattern may not be disease specific. The finding of reduced k , and mean

METABOLIC ANATOMY OF PARKINSON’S DISEASE

-6

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-2

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2

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31

B

1

, ,

/

-

2

-3

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1

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43

Clinical Asymmetry Score

FIG. 6. Clinicallpositron emission tomography correlations. A: clinical asymmetry scores related to left-right differences in striatal [‘8F]fluorodopa(FDOPA) uptake rate constants (Ki): positive clinical asymmetry scores correspond to predominantly right-side motor disability, and positive Kidifferences indicate relative reductions in right striatal FDOPA uptake; negative values reflect the predominantly left-side motor disability and reduced left striatal FDOPA uptake. There is a significant negative correlation between clinical asymmetry scores and left-right differences in Ki (r = -0.80, p = 0.00.5), indicating decreased FDOPA uptake contralateral to the more severely affected limbs. B: Clinical asymmetry scores related to W, pattern weights for metabolic asymmetry: positive W, values indicate regional increases in left hemispheric metabolism relative to the right; negative W, values indicate the opposite. A positive correlation (r = 0.82, p = 0.0003) between clinical asymmetry scores and W, was noted, indicating relative increases in basal ganglia and thalamic glucose metabolism contralateral to the more affected limbs.

rCMRGlc in PD patients is consistent with the results of previous FDGPET studies of parkinsonism (8), and is unlikely to be strictly an aging effect (47,48). The metabolic landscape of PD is best described by an analysis of regional patterns of hemispheric asymmetry. The application of SSM to the analysis

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of left-right asymmetries in PD patients reveals a distinct metabolic covariance pattern, P,, which includes 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 contralateral thalamic and basal ganglia mei abolism in asymmetric PD patients is consistent vith the notion of ‘‘metabolic release” of certain subcortical structures after nigral dopamine depletion. Previous PET studies of hemiparkinsonism have yielded mixed results with regard to metabolic asymmetries. Wolfson and colleagues (5) demonstrated a 10% coupled increase in rCBF and rCMRO, in the basal ganglia contralateral to the affected limbs in hemiparkisonian patients. Perlmutter and Raichle (6) described an abnormal asymmetry of pallidal blood flow in four hemiparkinsonian patients, but with relatively decreased contralateral pallidal rCBF in three. Martin et al. (9), using FDG/PET, described contralateral glucose hypermetabolism in two of four hemiparkinsonian patients, although the pallidal localization of the hypermetabolic focus was not demonstrated with certainty. In chronic PD patients, increases in basal ganglia metabolism after nigral dopamine loss may be of small magnitude and obscured by the heterogeneity of structure and function within a typical basal ganglionic ROI. Penney and Young (45) argued that major structural and functional inhomogeneities occur with the human striatum and that dopamine deficiency may give rise to excitation or inhibition of differing neuronal subpopulations. This structural and functional heterogeneity, which is particularly marked within the globus pallidus (44,45), may account for the inconsistent results of the previous PET studies. Because of their small magnitude, rCMRGlc asymmetries in PD patients may not be demonstrable by simple left-right comparisons (i.e., analysis of variance statistics). However, when left-right differences in the metabolic activity of basal ganglia subnuclei are linked to functional asymmetries in other brain regions, statistical techniques, such as SSM, can identify these patterns of regional covariation. By specifically restricting the

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search to regional patterns of hemispheric asymmetry, a small biological signal correlated with clinical and neurochemical asymmetries was extracted. Because clinical ratings and FDGiPET scans were performed on one occasion, and FDOPA/PET scans were performed on a separate occasion, the comparability of data derived from the two PET studies (and their clinical correlates) might be questioned. In non-levodopa-treated patients, the results of FDG/PET and FDOPA/PET studies are comparable in that they refer to identical clinical and pharmacologic states. The situation in levodopa-treated patients is more complex. First, withdrawing levodopa (to maximize FDOPA uptake at the time of PET scanning) may increase Ki relative to the levodopa-treated state. The pharmacokinetics of FDOPA uptake in levodopa takers is further complicated by the presence of 3-OMD, which may accumulate in plasma and cross the blood-brain barrier (49-51). It is conceivable that a steady-state increase in this metabolite might reduce regional PET count rates and lower derived K , values. Similarly, FDOPA uptake may be reduced by endogenous amino acid competitors (22), although plasma levels of seven potential transport competitors were not elevated in our patients. Our results suggest that, in spite of these difficulties, FDOPA uptake correlates with quantitative clinical and metabolic indices of disease severity, and that Ki, the derived FDOPA uptake rate constant, may be regarded as a characteristic property of the presynaptic nigrostriatal system rather than a variable related to a specific clinical-pharmacologic state. The lower striatal FDOPA uptake characteristic of our levodopa-treated patients may reflect the greater severity of their disease (52) rather than raised plasma levels of 3-OMD. Indeed, recent quantitative FDOPNPET studies demonstrate that 3-OMD at plasma levels typically encountered in levodopa-treated patients does not inhibit FDOPA access to the brain (53). This study demonstrates the feasibility of relating clinical symptomatology, particularly bradykinesia or motor asymmetries, to specific patterns of regional glucose metabolism in PD patients. With larger numbers of patients, it may be possible to link other motor and cognitive disturbances to the activity of discrete neuronal networks. Acknowledgment: The authors thank Dr. Fletcher McDowel1 for his support, and Mr. George Abramson and Ms. Karen Torello for manuscript preparation. This work

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was supported in part by National Institutes of Health grant NS-23473.

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