Journal of Cerebral Blood Flow and Metabolism

14:783--801 1994 The International Society of Cerebral Blood Flow and Metabolism
Published by Raven Press, Ltd., New York

The Metabolic Topography of Parkinsonism

D. Eidelberg, *J. R. Moeller, V. Dhawan, P. Spetsieris, S. Takikawa, T. Ishikawa,
tT. Chaly, tWo Robeson, tD. Margouleff, :j:S. Przedborski, and :j:S. Fahn
Department of Neurology, North Shore University Hospital/Cornell University Medical College, Manhasset,
*Department of Psychiatry, New York State Psychiatric Institute, Columbia College of Physicians and Surgeons,
New York, tDepartments of Medicine and Research, North Shore University Hospital/Cornell University Medical
College, Manhasset, and :f;Department of Neurology, Neurological Institute, Columbia College of Physicians and
Surgeons, New York, New York, U.S.A.

We used [lB F]fluorodeoxyglucose/positron

emission tomography eB F-FDG/PET) and a statistical
model of regional covariation to study brain topographic
organization in parkinsonism. We studied 22 patients with
Parkinson's disease (PD), 20 age-matched normal volun
teers, and 10 age- and severity-matched patients with pre
sumed striatonigral degeneration (SND). We used FDGI
PET to calculate global, regional, and normalized meta
bolic rates for glucose (GMR, rCMRglc, rCMRglc/GMR).
Metabolic parameters in the three groups were compared
using an analysis of variance, with a correction for mul
tiple comparisons, and discriminant analysis. The scaled
sub profile model (S SM) was applied to the combined
rCMRglc dataset to identify topographic covariance pro
files that distinguish PD patients from SND patients and
normals. GMR, rCMRglc, and rCMRglc/GMR were nor
mal in PD; caudate and lentiform rCMRglc/GMR was re
duced in the SND group (p < 0.01). S S M analysis of the
combined group of patients and normals revealed a sig
nificant topographic profile characterized by increased

metabolic activity in the lentiform nucleus and thalamus

associated with decreased activity in the lateral frontal,
paracentral, inferior parietal, and parietooccipital areas.
Individual subject scores for this profile were signifi
cantly elevated in PD patients compared with normals
and SND patients (p < 0.001) and discriminated the three
groups. In the PD group, subject scores for this factor
correlated with individual subject Hoehn and Yahr
(H&Y) scores (p < 0.02), and with quantitative rigidity (p
< 0.01) and bradykinesia (p < 0.03) ratings, but not with
tremor ratings. S S M analysis of right-left metabolic
asymmetries yielded a topographic contrast profile that
accurately discriminated mildly affected PD patients
(H&Y Stage I) from normals. Our findings demonstrate
that abnormal topographic covariance profiles exist in
parkinsonism. These profiles have potential clinical ap
plication as neuroimaging markers in parkinsonism. Key
B
Words: e F]Fluorodeoxyglucose-Metabolic topogra
phy-Parkinsonism-Positron emis sion tomography
Striatonigral degeneration.

Received May 24, 1 993 ; final revision received January 1 8 ,

1 994; accepted January 1 9 , 1 994 .
Addre s s correspondence and reprint reque sts to Dr. D .
Eidelberg, Department of Neurology , North Shore University
Hospital/Cornell University Medical College , 300 Community
Drive , Manhasset, NY 1 1030, U . S . A .
Abbreviations used: A N O VA , analysis o f variance ; CT , com
puted tomography ; dopamine , 3 ,4-dihydroxyphenylethylamine ;
FDG , ['8 Fjflu orodeoxyglu c o s e ; F D O P A , ['8 Fjfluoro- 3 ,4dihydroxyphenylalanine ; GMR, global metabolic rate for glu
cose ; GSF, global scaling factor ; H&Y , Hoehn and Yahr (1967) ;
MGP, medial pallidum ; MR!, magnetic resonance imaging; OM,
orbitomeatal ; PCA , principal-components analysis ; PD, Parkin
son' s disease; PDt, group with mild PD (H&Y Stages I-II); PD2 ,
group with advanced PD (H&Y Stages III-V); PET , positron
emission tomography ; rCMRglc' regional cerebral metabolic rate
for glucose ; 8rCMRglc left-right asymmetry index for rCMRg1c
'
in paired region s ; ROI , region of interest; SMA, supplementary
motor area; SND, striatonigral degeneration ; SSF, subject scal
ing factor; SSF" SSF2, and SSF3, SSF for Topographic Profiles
1 , 2, and 3, respectively ; S S Fc1 and SSFc2, SSF for Contrast
Profiles 1 and 2, respectively ; SSM, scaled sub profile model ;
STH , subthalamic nucleus ; UPDRS , Unified Parkinson Disease
Rating Scale 3 . 0 .

Although the primary biochemical pathology of

Parkinson'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 , 4-dihydroxyphenylethylamine (dopa
mine) system produce widespread abnormalities in
regional cerebral metabolism and blood flow
(Wooten and Collins, 1981; Crossman et aI., 1985,
1990; Porrino et aI., 1987; Palombo et aI., 1990).
Studies in patients with PD using positron emission
tomography (PET) have suggested increases in
basal ganglion metabolism (Martin et aI. : 1984;
Rougement et aI., 1984; Wolfson et aI., 1985; Eidel
berg et aI., 1990), as well as decreases in inferior
parietal and global metabolism, especially in pa
tients with dementia (Kuhl et aI., 1984; Peppard et
aI., 1990; Schapiro et aI., 1993). Nonetheless, re
gional and global metabolic changes have not been
fully reproducible across study populations, and the

Summary:

783

784

D . EIDELBERG ET AL .

relationship of these metabolic changes to indepen

dent indices of disease severity has not been closely
examined.
It is generally recognized that many of the behav
ioral manifestations of normal and pathological ner
vous system function are subserved by topograph
ically distributed networks of interacting brain re
gions (e. g. , Mesulam, 1981). These networks may
be represented as patterns of covariation among
spatially distributed brain regions and can be al
tered by behavioral activation or the presence of
disease. Specifically, normal regional covariance
patterns may be disrupted by the presence of local
ized pathology such as that occurring in neurode
generative disorders such as Alzheimer's disease
and PD. Several approaches have evolved to iden
tify and quantify these regional interactions. Princi
pal-components analysis (peA) has been used in
the analysis of PET data to contrast groups in the
same resting state (e.g. , Moeller et aI. , 1987; Rot
tenberg et aI. , 1987; Eidelberg et aI. , 1990; Sackeim
et aI. , 1 990) and, more recently, in brain activation
paradigms (McLaughlin et aI. , 1992; Friston et aI. ,
1993). peAs extract multiple independent compo
nents that, singly or in combination, account for the
majority of the variance in the regional PET data.
These principal components or topographic co
variance profiles can be construed as distributed
neural networks. The scaled subprofile model
(SSM), described by us previously (Moeller et aI. ,
1987 ; Moeller and Strother, 1991), applies peA to
combined populations of subjects (e. g. , patients and
normal control subjects) blind to subject groupings.
SSM extracts those principal components across
which there is maximal regional variability. Each
topographic profile is associated with an individual
subject score that quantifies the extent to which the
topographic profile is manifested by the subject.
SSM analyses have been applied previously to func
tional imaging data from a variety of neurodegener
ative and psychiatric disorders (Rottenberg et aI. ,
1987 ; Anderson et aI. , 1988; Eidelberg et aI. , 1990;
Sackeim et aI. , 1990, 1993).
In a preliminary attempt to identify abnormal re
gional covariation patterns in PD, we reported an
SSM analysis of eS F]fluorodeoxyglucose (FDG)
PET data from 14 patients with PD and 18 normal
control subjects (Eidelberg et aI. , 1990) . The results
suggested the presence in PD of abnormal topo
graphic profiles characterized by covarying basal
ganglia and thalamic increases in metabolism, most
evident in an analysis of right-left metabolic asym
metries. Individual subject scores for these profiles
correlated significantly with independent measures
of disease severity and with striatal eSF]fluoro-3,4J Cereb Blood Flow Metab, Vol. 14, No. 5, 1994

dihydroxyphenylalanine (FDOPA) uptake rate con

stants. This study was limited by the low resolution
of the PET tomograph, and basal ganglia metabolic
activity could not be subdivided into smaller subre
gions, such as the caudate and lentiform nuclei. In
addition, several of the patients with PD received
levodopa at the time of the PET study and the nor
mal control subjects were not age-matched.
In this study we sought to validate and expand
upon the previous findings by examining FDG/PET
data derived from a larger, entirely new cohort of
medication-free PD patients and age-matched con
trols using a higher-resolution tomograph. Topo
graphic profiles from the new population were com
pared with those derived previously. To assess the
potential of these profiles to serve as disease
specific markers, we correlated the individual sub
ject profile weights with independent clinical ratings
across a broad range of disease severity. We also
explored the potential for early disease detection by
performing discriminant analyses between normals
and patients at a stage of mild, early disease.
Another aim was to explore the broader applica
tion of SSM in functional imaging studies of the
akinetic-rigid movement disorders. We have re
ported 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 (Eidelberg et aI. , 1993). By
adding a sample of patients with SND to a com
bined sample of age-matched normal control sub
jects and age- and severity-matched patients with
PD, we sought to determine whether SND was as
sociated with a different topographic profile than
PD or whether the same topographic profiles were
affected in both parkinsonian disorders. In addition,
this three-group analysis allowed us to explore the
applicability of SSM analyses in the differential di
agnosis of clinically similar but pathologically dis
crete neurodegenerative disorders.
MATERIALS AND METHODS
Subjects

The following subject groups were studied with quan

titative FDGIPET.
Normal Subjects. We studied 20 normal volunteer sub
jects (10 men and 10 women; mean age S D , 47.0 17.1
years) recruited by advertisement among the hospital per
sonnel of North Shore University Hospital/Cornell Uni
versity Medical College and the spouses of PD patients in
local support groups. The following exclusion criteria
were used: (a) a history of neurological or psychiatric
illness; (b) prior exposure to neuroleptic agents or drug
use; (c) a medical history of hypertension, cardiovascular

785

THE METABOLIC TOPOGRAPHY OF PARKINSONISM

disease, and diabetes mellitus; and (d) an abnormal neu
rological examination.
Patients with PD. We studied 22 idiopathic PD patients
without dementia (12 men and 10 women; age, 57.9
11.4 years). A diagnosis of PD was made if the patient had
"pure" parkinsonism without a history of known caus
ative factors such as encephalitis or neuroleptic treat
ment; did not have early dementia, supranuclear gaze ab
normalities, or ataxia; and did have a convincing re
sponse to levodopa [20% change in composite Unified
Parkinson Disease Rating S cale (UPDRS) 3.0 motor
scores (items 19-31) (Fahn et aI., 1987)]. In all patients
family histories were negative for neurodegenerative ill
nesses. Magnetic resonance imaging (MRI) was per
formed in 18 of 22 patients and computed tomography
(CT) scanning in 4 of 22 patients. High-field strength T2weighted MRI (echo time, 80 ms; repetition time,
1,500 ms; field strength, 1.0 T) disclosed a normal
putamenal signal in all cases studied. Visually evident
cortical or subcortical atrophy was absent in all patients.
Patients were selected with a range of clinical severity
according to their Hoehn and Yahr (H&Y) (1967) ratings.
Five patients were selected in each of H&Y Stages I-IV
and two patients in H&Y Stage V. (Patient representation
in the latter category was limited by the technical diffi
culty associated with scanning markedly disabled ad
vanced patients.) To facilitate comparisons between mild
and moderate-severe patients, the PD group was subdi
vided into two subgroups (Table 1): The mild group (PD1:
H&Y Stages I-II) consisted of 10 patients (5 men and 5
women; age, 53.0 9.9 years; mean disease duration, 4.4
3.0 years). The advanced group (PD2: H&Y Stages
III-V) consisted of 12 patients (7 men and 5 women; age,
61.9 11.2 years; mean disease duration, 11.5 6.1

TABLE 1.

Patient No.
(age ; yr)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22

(45)
(48)
(48)
(6 1 )
(69)
(4 1 )
(47)
(49)
(53)
(69)
(45)
(57)
(62)
(7 1 )
(72)
(4 1 )
(62)
(63 )
(63 )
(64)
(60)
(73 )

years). The clinical characteristics of these PD patients

are given in Table 1.
Patients with SND. We studied 10 patients (8 women
and 2 men; age, 61.8 6.9 years) with clinical findings
compatible with SND (Fearnley and Lees, 1990). The
clinical characteristics of these 10 SND patients and their
case histories have been reported by us elsewhere (Eidel
berg et aI., 1993). All patients presented with progres sive
limb rigidity and bradykinesia associated with early im
pairment of balance and gait and without ataxia, supra
nuclear gaze abnormalities, or dementia. Motor symp
toms were refractory to levodopa and dopamine agonists
(daily dose, 1,000 mg levodopa equivalents; :;;;15%
change in composite UPDRS motor scores). Transient or
minimal levodopa responses were evident in four of these
patients. Six of the SND patients were on chronic levo
dopa therapy up to the time of PET imaging; the remain
der were off medication for at least 2 weeks prior to scan
ning. MRI was performed on eight patients and CT on
two patients. High-field strength T2-weighted MRI (echo
time, 80 ms; repetition time, 1,500 ms; field strength,
1.0 T) disclosed patchy putamenal loss of signal in four
of eight patients. Mild brain-stem atrophy was noted in
one patient; cortical atrophy was absent in all patients.
Metabolic data on the 10 SND patients, 15 of 22 PD pa
tients, and 10 of 20 normal subjects have been reported by
us previously (Eidelberg et aI., 1993).
PET

The patients and volunteers fasted overnight prior to

FDGIPET scanning. In all PD and SND patients, all an
tiparkinsonian medications were discontinued at least 12
h before PET was conducted. At the time of PET study,
all PD and SND patients were rated quantitatively ac-

PD patients
UPDRS ratinga

Duration
(yr)

H&Y
Stage

BK

6
7
5
1
7
1
6
4
11
1
5
8
3
23
11
11
14
7
17
13
9
24

I
I
I
I
I
II
II
II
II
II
III
III
III
III
III
IV
IV
IV
IV
IV
V
V

2
2
3
3
2
3
1
5
7
5
13
7
8
4
2
11
15
7
11
8
20
8

2
2
0
2
2
1
6
5
1
3
1
0
0
0
0
8
1
5
6
1
1
6

1
0
2
1
1
4
4
1
2
5
2
4
8
1
2
1
9
9
5
2
18
7

3
-4
5
6
5
4
4
-4
-4
-5
4
-1
-2
2
2
-3
-3
2
2
1
1
-2

Medication(s)b
4
1, 4
1, 4
1, 4
1, 4
3
3
5
1 , 2,
3, 4
1, 2
1, 2
1
1 , 2,
1 , 2,
1 , 3,
1 : 2,
1 , 2,
1
1 , 2,
1 , 2,
1, 2

3, 4
3, 4
4
4
4
4
4

UPDRS summed clinical scores for bradykinesia (BK), tremor (T), and rigidity (R). Asymmetry (A) is the right-left difference in the
sum of the individual unilateral limb score s . Positive and negative values , respectively, denote right- and left-sided clinical predomi
nance.
b ( 1 ) Levodopa/carbidopa ; (2 ) dopamine2 agonists ; (3 ) anticholinergics ; (4) monoamine oxidase inhibitors ; (5) none .
a

J Cereb Blood Flow Metab. Vol. 14. No.5. 1994

786

D . EIDELBERG ET AL .

cording to the H&Y and UPDRS scales. PET studies

were performed using the Superpett 3000 tomograph
(Scanditronix; Essex, MA, U.S.A.). The performance
characteristics of this instrument have been described
elsewhere (Robeson et aI., 1993). This four-ring BaF2
time-of-flight, whole-body tomograph acquires 14 PET
slices with Z-axis translation. Each slice is 8 mm thick
and reconstructed with a transaxial resolution of 8 mm
(full width at half-maximum). Ethical permission for these
studies was obtained from the Institutional Review Board
of North Shore University Hospital/Cornell University
Medical College. Written consent was obtained from each
subject following a detailed explanation of the proce
dures.
Patients were positioned in the scanner in a custom
molded headrest (Alpha Cradle; Smithers Medical, Tall
madge, OH, U . S . A.) ( K e arfo tt, 1984) with three
dimensional laser alignment with reference to the orbito
meatal (OM) line. A cylindrical tube filled with 68Ge was
placed in the field of view to provide internal calibration
for each slice. All studies were performed with the sub
ject's eyes open in a dimly lit room and minimal auditory
stimulation. FDG was produced using the radiochemical
synthesis of Chaly and colleagues (1990). Subjects re
ceived 5-10 mCi of FDG by intravenous injection. The
time course of plasma 18F radioactivity was determined
by sampling radial arterial blood followed by centrifuga
tion. PET images were reconstructed with a correction
for tissue attenuation of 511 ke V of 'Y radiation measured
with an external 68Ge ring source. PET reconstructions
were also corrected for random coincidences, electronic
dead time, and tissue attenuation. A single scalar correc
tion was used to compensate for scatter effects in trans
mission, cross-calibration, and emission scans (Robeson
et aI., 1993).
We calculated global and regional metabolic rates for
glucose (GMR and rCMRglc, respectively) in all FDGI
PET studies using autoradiographic scans (Phelps et aI.,
1979) acquired for 20 min beginning 35 min postinjection,
with estimated mean normal rate constants [k1
0.1056,
k2
0.1584, k3
0.0904; k4 was fixed at 0.0068 (Dhawan
et aI., 1989; Eidelberg et aI., 1993; Robeson et aI., 1993)].
To facilitate comparisons with our previous metabolic
data, we chose a lumped constant of 0.42.
Region-of-interest (ROI) analysis was performed on
256 x 256 PET reconstructions using a SUN microcom
puter (490 SPARC Server; Sun Microsystems, Mountain
View, CA, U.S.A.) with ScaniVP Software (Spetsieris et
aI., 1993). To compare regional values with those re
ported by us earlier (Eidelberg et aI., 1990, 1993), we
defined 26 (13 per hemisphere) standardized cortical and
subcortical gray matter ROIs and two cerebellar and two
brain-stem ROIs. ROIs were defined interactively on re
constructed PET slices by visual inspection with refer
ence to a standard neuroanatomical atlas (Talairach and
Tournoux, 1988) and MRI or CT when available. Mean
ROI size ranged from 40 pixels for the caudate nucleus to
350 pixels for the lateral frontal and temporal cortical
2
regions (1 pixel
4 mm ). To reduce partial volume ef
fects, we calculated "peak" rCMRglc values by averaging
the upper 20% of ROI pixel values (Rottenberg et aI.,
1991). Whenever anatomical regions straddled contiguous
PET slices, the rCMRglc was calculated by weighting
component ROI values by the number of thresholded pix
els on each slice. The GMR was calculated as the mean of
the rCMRglc values weighted by the total number of
=

J Cereb Blood Flow Metab, Vol. 14, No. 5, 1994

thresholded pixels in each ROI. To reduce intersubject

variability, regional metabolic measurements were nor
malized by global values (rCMRglc/GMR). We also calcu
lated a right-left asymmetry index (orCMRglc) for each
paired region defined as (L - R)/(L + R) x 100%, where
L and R refer to left and right homologous rCMRglc val
ues, respectively.
Statistical analyses

Glucose Metabolism. The following statistical proce

dures were employed for between-group comparisons. (a)
We compared GMR and rCMRglc and GMR-normalized
regional values (rCMRglc/GMR) for the various clinical
groups using analysis of variance (ANOV A) followed by
post hoc group comparisons using the Tukey-Kramer
HSD adjustment (Winer, 1971). This procedure was ap
plied separately to all the individual regional values (30
rCMRgic and 30 rCMRglc/GMR measurements) and to the
GMR. (b) To identify the regional values that maximally
discriminate the various groups, we employed stepwise
discriminant analysis using the F test associated with
Wilks' A (Anderson, 1984). The p values are reported
incorporating the Bonferroni correction for the number of
regional comparisons. Differences between groups were
considered significant when comparisons exceeded 95%
confidence limits (p < 0.05).
In this study we performed two separate sets of be
tween-group comparisons: In the first analysis, we com
pared the metabolic parameters derived for the entire typ
ical PD (n
22) and normal control (n
20) samples. In
the second analysis, we performed a three-group compar
ison of the metabolic parameters measured in the entire
SND sample (n
10; mean age, 61.8 6.9 years; mean
H&Y score, 3.5 0.8), an age- and severity-matched
subset of the PD2 sample (Patients 11-18, 22, and 23; n
10; mean age, 60.6 10.8 years; mean H&Y score, 3.7
0.8), and an approximately age-matched normal control
samples (n
10; mean age, 57.6 12.6 years). Identical
statistical procedures were carried out for each set of
between-group comparisons.
SSM: Methodology. To determine whether specific
patterns of regional metabolic covariation distinguished
the groups, patient and normal control rCMRglc datasets
were analyzed using SSM. The mathematical properties
of this model, its statistical assumptions, and its compu
tational procedures have been d e scribed elsewhere
(Moeller et aI., 1987; Moeller and Strother, 1991; Sackeim
et aI., 1993). This statistical model proposes that, for each
subject, each regional rCMRglc value is comprised of two
basic elements. (a) A diffuse or regional-independent
scaling factor (global scaling factor; GSF) modulates or
scales all regional values for a given individual. The GSF
is similar to the GMR, but the contributions of the topo
graphic profiles are removed in the calculation of the
GSF. (b) Independent sets of topographic profiles corre
spond to different patterns of covariance among brain
regions. The contribution of a particular brain region to a
topographic profile, i.e., its relative importance in the
covariance relationships within the profile, is quantified
by its regional weight in the corresponding topographic
profile. Therefore, the topographic profile is a vector of
regional values representing the covariance relationships
among the brain regions. Because different individuals
manifest these relationships to greater or lesser degrees,
the SSM computes a subject score (subject scaling factor;
=

787

THE METABOLIC TOPOGRAPH Y OF PARKINSONISM

SSF) to quantify individual differences in manifesting
each topographic profile.
All S S M parameters were derived by applying the
model to the data from the total sample, blind to group
membership. The computations involved subtracting
from each subject' s regional values the mean value at
each region, determined acros s the total sample. These
difference scores produced the approximation to the sub
ject x region variance. A PCA was performed on the
transposed covariance matrix of these difference scores
to extract a set of principal (unrotated) components. The
region weights on each principal component described a
topographic covariance profile. The subject scores for a
principal component (PCA scalars or SSFs) quantified the
extent to which the topographic pattern was manifested
by the individual subject. The number of principal com
ponents to retain was determined by applying the Scree
test (Stevens, 1986) to the set of eigenvalues and by ex
amining the extent to which the SSFs accounted for the
variance in GMR values. The GSF was computed for
each subject using multiple regression analysis to predict
global mean rCMRglc values on the basis of the SSFs. The
GSF corresponded to the residual between predicted and
obtained values. Adding the intercept term to the residu
als produced the final form of the GSF in the original
rCMRglc units.
In addition, a separate analysis of right-left metabolic
asymmetries was performed using the orCMRgJc meta
bolic asymmetry measures. This procedure is computa
tionally identical to the SSM analysis of the hemispheric
rCMR gic data d e scribed above. Howe ver, by using
orCMRgl C values, this SSM analy sis identifies topo
graphic contrast profiles representing covariance patterns
of regional metabolic asymmetry whose contribution may
vary across the subjects analyzed within the total sample.
To determine whether the groups differed on the SSM
parameters of GMR (GSF) or topographic organization
(SSFs), the same ANOV A procedures and discriminant
analyses were applied as described above for the rCMRglc
datum analysis. The p values were corrected for multiple
SSF and GSF comparisons using an ordered Bonferroni
procedure with ranking by eigenvalue (Rosenthal and Ru
bin, 1984).
SSM: Clinical Correlations and Topographic Profile
Comparisons. Clinical-metabolic correlations. Pearson
product-moment correlations were computed to examine
the relationship between the clinical and the metabolic
measures. The following clinical parameters were used in
these correlations: H&Y scores, individual UPDRS mo
tor scores for tremor, rigidity, bradykinesia, posture, and
gait, and a composite motor score defined as the sum of
items 19-31 in the UPDRS (Fahn et aI., 1987). We also
calculated a limb asymmetry index defined by right-left
differences in individual limb UPDRS scores (Eidelberg
et aI., 1990). Because these clinical scores may be closely
correlated within individual subjects, we performed a
pairwise correlational analysis of the individual scores to
identify interrelated subsets of scores (Eidelberg et aI.,
1990). H&Y scores, composite UPDRS motor scores,
mean values of intercorrelated subsets of scores, and in
dividual UPDRS scores were correlated with the follow
ing metabolic measures: (a) rCMRgJc and rCMRglc/GMR
for all 30 right- and left-hemispheric and brain-stem ROIs;
(b) SSFs for the various topographic profiles; and (c) the
global metabolic measures, GMR and GSF. The p values
were corrected for the number of independent clinical-

metabolic correlations performed and were considered

significant when <0.05.
Topographic profile comparisons. Reproducibility. We
compared the results of this SSM analysis to those de
scribed by us in an earlier analysis of an entirely different
sample of PD patients and normal control subjects (Ei
delberg et aI., 1990). Specifically, we performed separate
SSM analyses of combined rCMRglC data from the normal
controls and PD patients comprising each of the two
study populations. Region weights on the individual to
pographic profiles derived in the two analyses were com
pared using correlation analysis.
Comparison of parkinsonian subtypes. To explore the
potential applicability of SSM in the differential diagnosis
of clinically similar but pathologically discrete movement
disorders, we performed this procedure on rCMRgJc data
from a combined three-group cohort containing the 10
SND patients, the 10 age- and severity-matched PD2 pa
tients, and 10 age-matched normal subjects (n
30). This
analysis allowed us to determine (a) whether including
SND patients in the SSM analysis introduced a new to
pographic profile that was not evident in the original two
group analysis of the full normal control and PD cohorts
(n
42), (b) whether the same topographic profiles ex
tracted previously were also identifiable in this three
group analysis, and (c) whether SND patients can be dif
ferentiated from PD counterparts of similar age and dis
ease severity based upon subject scores for one or more
of the topographic profiles identified in the SSM analysis.
To address these questions, we used correlation analysis
to compare the region weights on the topographic profiles
identified in the three-group analysis with the correspond
ing regional values derived in the original two-group anal
ysis. Similarly, SSF values for the various topographic
profiles derived in the two sets of between-group analyses
were correlated in the 20 subjects (10 PD patients and 10
normal subjects) common to both analyses. GSF and SSF
values for the three groups included in this S S M analysis
were compared using the ANOVA procedures and dis
criminant analyses described above. All statistical analy
ses were carried out using SAS (SAS Institute, Cary, NC,
U.S.A.).
=

RESULTS
Glucose metabolism

Mean rCMRglc/GMR and GMR values for the PD,

SND, and normal control groups are given in Ta
ble 2. In the SND group, caudate and lentiform
rCMRglc/GMR values were significantly reduced
compared with those of age-matched normals and
age- and severity-matched PD patients (p < 0.01).
The parkinsonian groups did not differ from the nor
mals in any other measure of regional or global me
tabolism (p > 0.05 for all comparisons).
SSM: topographic profiles

SSM analysis of the rCMRglc data from the com

bined group (n
42) disclosed three significant to
pographic profiles that accounted for 47 . 1% of the
subject ox region variance. Individual differences in
manifesting these three topographic profiles (SSFs)
=

J Cereb Blood Flow Metab, Vol. 14, No.5, 1994

788

D . EIDELBERG ET AL.
TABLE 2.

rCMRg1c and GMR (mg min-I 100 g-I)

Mean (SD)

Cerebellum
Pons
Midbrain
Caudate
Lentiform
Thalamus
Med. temporal
Lat. temporal
Operculum
Sup. temporal
Med. frontal
Lat. frontal
Calcarine
Cuneus
Inf. parietal
Paracentral
GMR

Normal
(n = 20)

PD 1
(n = 1 0)

7 . 570. 1 1 )
5 . 1 1 (0 .90)
5 . 89 ( 1 . 24)
7 . 89 ( 1 . 2 1 )
8 . 6 1 0 . 1 9)
7 . 78 ( 1 . 14)
6 . 09 ( 1 . 15)
7 . 54 ( 1 . 3 1 )
8 . 75 ( 1 .44)
9 . 06 ( 1 . 55)
8 . 020.33)
8 . 78 ( 1 . 52)
1 0 . 24 ( 1 . 62)
9.91 (1 .61)
8 . 5 1 ( 1 . 28)
7 . 85 ( 1 . 14)
8 . 35 ( 1 . 25)

6.93 ( 1 . 14)
4 . 85 0.06)
5 . 75 (1 . 1 8)
7 . 28 (1 .03)
8 . 20 ( 1 . 1 6)
7 . 54 (1 .04)
5 . 64 (1 . 0 1 )
7 . 27 ( 1 . 22)
8 . 04 ( 1 . 1 7)
8 . 55 ( 1 . 22)
7 . 340. 39)
7 . 89 ( 1 . 36)
9 . 30 ( 1 . 8 1 )
8 . 84 (2.09)
7 . 87 ( 1 . 30)
6 .42 (2 .53)
7 . 82 ( 1 . 22)

PD2
(n = 12)
6.51
4 . 38
4 . 54
6.21
7 . 36
6.38
4.88
5 . 55
6.40
6 .95
5 . 87
6.21
7 . 58
6 . 96
6 . 24
5 . 78
6.41

SND

(n = 1 0)

(0 .94)
(0 . 68)
(0 .83)
( 1 .07)
( 1 . 30)
(0 . 78)
(0 . 89)
( 1 . 29)
(0 . 87)
( 1 . 1 0)
(0 . 89)
(0 .92)
( 1 . 50)
( 1 . 24)
(1 . 1 1)
( 1 . 04)
(0 . 89)

6 . 62
4.40
5 . 09
5 . 96
6.15
6.04
5 .95
6. 17
6 .45
6 .03
5 . 63
6.07
6 . 63
6.77
7 .06
7 . 60
7 . 02

(1 .01)
(0 . 60)
(0 . 68)
(0 . 85)
( 1 .06)
( 1 . 02)
( 1 .05)
(0 . 69)
(0 .78)
(0 . 76)
(0 . 7 1 )
(0 . 68)
(0 . 75)
(0 . 84)
(0 . 86)
(0 . 85)
(0 .70)

Med., medial ; lat., lateral ; sup., superior; inf., inferior.

accounted for 43 .7% of the variance in GMR. This

indicated that a substantial portion of GMR vari
ability was due to individual differences in these
major topographic effects. When the topographic
effects were removed, a region-independent global
measure (GSF) was calculated. The PD and normal
groups did not differ in GSF, suggesting that the
two groups differ primarily in the representation of
the topographic profiles.
The region weights on the three significant topo
graphic profiles are presented in Table 3. SSF valTABLE 3.

ues for the various profiles were z-transformed and

offset to a mean of zero for the normal control pop
ulation. (Scalar adjustments in subject scores do not
influence between-group statistical comparisons or
clinical correlations because all members of the
samples are shifted equally.) Thus, individual SSFs
were interpreted relative to an adjusted metabolic
baseline defined by the normal control population.
Additionally, the polarity of the profiles was ori
ented so that the mean SSFs for the PD group had
positive values and positive subject x region pro-

Region weights on the three bihemispheric topographic profiles

Profile

Pons
Midbrain

2.11
0.42

Profile

0.79
-2.08

-0 .40
1.31

Left hemisphere
Cerebellum
Caudate nucleus
Lentiform nucleus
Thalamus
Med. temporal
Lat. temporal
Operculum
Sup. temporal
Med. frontal
Lat. frontal
Occipital
Parietooccipital
Inf. parietal
Paracentral

1.52
0.46
1.22
1.04
-0. 27
-1.47
-0 . 5 5
-0 . 1 8
-0 . 74
-1.20
-0 . 29
-1.31
-0 .95
-1.15

0 . 86
0.12
-0 .78
-0 . 1 9
-1.39
-1 . 01
0.14
-0 .06
-0 . 1 3
0.20
2 .13
1.11
1.16
-0 .60

Right hemisphere
0 . 69
0. 1 1
-0 .62
-0. 3 5
1.53
1.19
-1.28
-0 .75
-1.36
-0 .37
-0 . 1 8
1.67
0 .95
-1.19

1.66
0 . 84
1.49
0.78
0.81
-0 .58
-0 .48
0.49
-0 . 65
-0 .86
-0 .42
-0 .97
0 . 03
-0 .79

1.34
-0 .43
-0 .70
-0 . 1 0
-1 .12
-1.73
-0 . 04
-0. 1 5
-0 .23
-0 . 1 3
1.99
0 . 86
0 . 65
-0 .47

The topographic profiles were identified by SSM analysis of bihemispheric rCMRglc data
combined group of 22 PD patients and 20 normal control subjects. Positive and negative
indicate regions of relative metabolic increases and decreases, respectively. Region weights
italicized ; those also associated with motor control networks are boldfaced. Med., medial ; lat.,
sup., superior; inf., inferior.

J Cereb Blood Flow Metab, Vol. 14, No. 5, 1994

0.91
-0 . 24
-0 .88
-0 . 3 1
0.79
1 . 03
-1.05
0.08
-1.34
-0 .59
-0 . 28
1 .3 8
1 .23
-1.69
from a
values
;;. 1 are
lateral ;

789

THE METABOLIC TOPOGRAPH Y OF PARKINSONISM

files (Moeller and Strother, 1991; Sackeim et aI.,
1993).
The following topographic profiles were identi
fied in the analysis of bihemispheric rCMRgJc data
(n = 42):
Topographic Profile 1. This topographic profile
(20.7% variance accounted for; V AF) was charac
terized by increased activity of the cerebellum,
pons, lentiform nucleus, and thalamus associated
with covariate decreased activity of the lateral fron
tal, paracentral, and parietal association cortices.
(Calcarine activity did not contribute to this covari
ance pattern, defining a reference point with which
to compare the activity of the other regions.) An
isometric display of this pattern is presented in Fig.
1. Subject scores for this profile (SSF I) were signif
icantly higher for the entire PD group compared
with the normals (p < 0.001). The mean SSF1 was
significantly higher in the PD2 subgroup compared
with the PDI subgroup and the normal controls (p <
0.01 for both comparisons) (Fig. 2). SSF1 discrimi
nated the PD group from the normals [F(1,40) =
14.9, p < 0.001] , specifically separating the ad
vanced PD2 subset [PD1 vs. normal, F(1,28) = 1.1,
nonsignificant; PD2 vs. normal, F(1, 30) = 36.0, p <
0.0002].
Topographic Profile 2. This topographic profile
(15.9% VAF) was characterized by increased activ
ity in the calcarine cortex and in the inferior parietal
and parietooccipital areas. This was associated with
decreased activity of the midbrain and medial and
lateral temporal areas. Mean subject scores for this
profile (SSF2) did not differ between or discriminate
the PD and the normal groups.
Topographic Profile 3. This topographic profile
(10.4% V AF) was characterized primarily by de
creases in medial frontal and paracentral activity
associated with increased parietooccipital and tem
poral lobe activity. Mean SSF3 values did not differ
in the two groups.
The following topographic contrast profiles (Ta
ble 4) were identified in the analysis of the regional
asymmetry (8rCMRgJc) data (n = 42) .
Contrast profile 1. This contrast profile (14.0%
V AF) was characterized by thalamic asymmetries
covarying with reciprocal polarity with asymme
tries in the paracentral cortex. Mean subject
weights for this contrast profile (SSFcl ) were signif
icantly higher than normal for the H&Y Stage I pa
tients (p < 0.02) but not for PD patients with more
advanced disease (Fig. 3). SSFc l values discrimi
nated H&Y Stage I patients from normals [F(1,23)
= 25.5, p < 0.0002] correctly identifying 5 of 5
H&Y Stage I patients and 18 of 20 normals. (The
two misidentified normals were aged 27 and 43

years.) SSFc l discriminated H&Y Stage I patients

from those with more advanced disease less accu
rately [F(1,20) = 4.9, p < 0.05].
Contrast profile 2. This contrast profile (9.6%
V AF) was characterized by thalamic and lentiform
asymmetries covarying with reciprocal polarity
with asymmetries in the caudate nucleus. Mean
subject weights for this contrast profile (SSFd did
not differ or discriminate among the normal and PD
groups.
SSM: clinical correlations and topographic
profile comparisons

Clinical-Metabolic Correlations . Glucose metab

olism. Correlation analysis of PD clinical scores re

vealed a strong pairwise correlation (r > 0.6, p <

0.001) between individual UPDRS scores for
bradykinesia, rigidity, and gait, composite UPDRS
motor ratings, and H&Y scores. Tremor ratings
were not significantly associated with these other
ratings (r < 0 . 32) . We therefore considered brady
kinesia, rigidity, and gait UPDRS scores to repre
sent a discrete subset of interrelated clinical ratings,
designated subset A. In the PD group, GMR corre
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 individual UPDRS ratings for bradykine
sia (r = -0.63, p < 0.005) and rigidity (r = -0.52,
p < 0.05). GMR did not correlate with ratings for
tremor, patient age, or disease duration (p > 0.1 for
all correlations). In the PD group, regional meta
bolic measures (rCMRgIC and rCMRgJc/GMR) did
not correlate with age, H&Y scores, or any of the
individual or composite ratings comprising the
UPDRS (p > 0.1 for all correlations).
SSM descriptors. In the PD group, GSF failed to
correlate with clinical severity measures. This sug
gests that the GMR correlations were due primarily
to the contribution of topographic rather than global
effects. In PD patients, SSF1 correlated signifi
cantly with age (r = 0.49, p < 0.04), H&Y ratings (r
= 0.61, p < 0.02), composite UPDRS motor ratings
(r = 0 . 56, p < 0.03), and subset A mean ratings (r
0.63, p < 0.01), as well as with individual UPDRS
ratings for bradykinesia (r = 0.56, p < 0.03) and
rigidity (r = 0.62, p < 0.01) (Fig. 4). No correlation
was evident between SSF1 values and tremor rat
ings (r
0.06) or disease duration (r
0.38). Nei
ther SSF2 nor SSF3 values correlated with any of
the clinical measures (p > 0.2 for all correlations).
SSFc2 values, obtained from the asymmetries anal
ysis, correlated with limb asymmetry scores (r =
-0.53, p < 0.04). SSFC I values did not correlate
with this parameter.
=

J Cereb Blood Flow Metab. Vol. 14, No. 5, 1994

790

D. EIDELBER G ET AL .

(A)

FIG. 1. Isometric display (Spet

sieris et aI., 1993) of the region
weights for Topographic Profile
1 on representative transverse
brain slices acquired approxi
mately 40 mm (A), 60 mm (B),
and 70 mm (C) above the OM
line. The insets (lower left) indi
cate the positions of the mid
lines of these transverse slices
on a standardized parasagittal
two-dimensional display. Rela
tive hypermetabolism (color
scale) of the lentiform nuclei
and thalamus is shown in A.
Relative hypometabolism (gray
scale) of the lateral frontal, infe
rior parietal, and parietooccipi
tal areas is evident in B, and
paracentral hypometabolism
in C.

(B)

J Cereb Blood Flow Metab, Vol. 14, No.5, 1994

THE METABOLIC TOPOGRAPHY OF PARKINSONISM

791
(C)

FIG. 1.

790.

C:

see legend on page

Topographic Profile Comparisons. Reproducibil

ity. To examine the reproducibility of these topo

graphic profiles across study populations, we cor

related the region weights on these patterns with
those derived in our earlier study of a different
group of PD patients and normal controls (Eidel
berg et al. , 1990) . Each of the three major topo
graphic profiles derived from bihemisphere analysis
was highly correlated between the two study popu-

lations. (Topographic Profile 1, r = 0 . 74; Topo

graphic Profile 2, r = 0 . 80; Topographic Profile 3, r
0 . 78; p < 0 . 0001 for all correlations) . This indi
cates that the reported bihemispheric topographic
profiles are reproducible in different PD patient
populations under varying tomographic imaging
conditions. Of the two significant topographic con
trast patterns derived through asymmetries analy
ses, Contrast Profile 1 alone was correlated in the
=

2
FIG. 2. Scatter diagram showing the SSF1
scores (see text) in normals (0) and in the P01
(.) and P02 (A) subgroups. M ean valuEls (::SO)
are displayed by vertical bars. SSF1 values were
significantly increased in the P02 subgroup
compared with the P01 subgroup and normals.

u..

CJ)
CJ)
0

tl

-1

-2
NORMAL

PD1

J Cereb Blood Flow Metab. Vol. 14, No.5. 1994

792
TABLE 4.

D . EIDELBERG ET AL .
Region weights on the two topographic
contrast profiles
Profile
2

Cerebellum
Caudate
Lentiform
Thalamus
Med. temporal
Lat. temporal
Operculum
Sup. temporal
Med. frontal
Lat. frontal
Occipital
Parietooccipital
Inf. parietal
Paracentral

-0. 1 9
-0.60
0.5 1
-2.30
1.76
-0.55
-0.0 1
-1.24
0.55
-0.05
0.69
0.50
-0. 1 0
1.04

-0.84
1.85
-0.67
-1.76
-1.80
0.21
0.32
0.20
0.42
0.06
0.86
0.30
0.93
-0.09

The topographic contrast profiles were identified by SSM anal

ysis of 8rCMRglc data from a combined group of 22 PD patients
and 20 normal control subjects. Positive and negative values
indicate the relative laterality of the regional metabolic asymme
tries (see text). Region weights :;;. 1 are italicized ; those also as
sociated with motor control networks are boldfaced. Med., me
dial ; lat., lateral ; sup., superior ; inf., inferior.

two datasets (r = 0. 71, p < 0.01). Contrast Profile

2 in the current study did not correlate with the
asymmetries profiles extracted in the earlier data
set.
Comparison of parkinsonian SUbtypes. SSM anal
ysis of a combined group of 10 SND patients, 10
age- and severity-matched PD patients, and 10 age
matched normal controls revealed three significant
topographic profiles accounting for 57.6% of the
subject x region variance. Neither of the global met
abolic measures, GMR or GSF, differed among the
three groups (p > 0. 3 for all comparisons). Region
weights on the three major topographic profiles
were highly correlated with region weights on the
corresponding three profiles identified in the two
group analysis (Topographic Profile 1, r = 0.76, p <
0. 000 1 ; Topographic Profile 2, r = 0. 86, p < 0. 0001 ;
Topographic Profile 3, r = 0. 49, p < 0.005). Simi
larly, SSFs for these three profiles were highly cor
related with values calculated for the same subjects
examined in the two-group analysis (SSF I' r =
0. 73, p < 0.0005 ; SSF2 , r = 0. 88, p < 0.0001 ; SSF3 ,
r = 0. 66, p < 0. 002). Thus, the addition of a second
distinct parkinsonian group to the SSM analysis did
not introduce a new major topographic profile, nor
did it distort the topography of the PD-associated
profiles described above.
Figure 5 displays the SSF values for each of the
three topographic profiles identified in the com
bined three-group analysis comprising the PD,
SND, and normal control groups. Comparison of
the SSFs for the three groups indicated that PD and
J Cereb Blood Flow Me/ab, Vol. 14, No. 5, 1994

SND differed from one another in the polarity and

magnitude of representation of these profiles. SSF 1
values were significantly greater in the PD group
compared to the SND group (p < 0.001). SSF1 dis
criminated the two parkinsonian groups [F(1, 18) =
32. 2, p < 0. 0002], correctly identifying 9 of 10 pa
tients in each of the PD and SND clinical catego
ries. Mean SSF2 values did not differ in the three
groups. Mean SSF3 values were not significantly
different in the PD and SND groups. Without Bon
ferroni correction for mUltiple SSF comparisons,
we noted an abnormal elevation of SSF3 values in
the SND group (p
0.03), with a trend toward an
abnormal elevation (p = 0. 06) in the PD2 group.
These SSF3 abnormalities did not reach significance
with Bonferroni correction.
=

DISCUSSION

In this report we demonstrate the utility of PCA

approaches, specifically SSM, in the analysis of
combined regional metabolic data from PD patients
and normal controls. We found a reproducible, dis
tinctive set of topographic covariance profiles that
correlated with independent clinical measures of
disease severity. In the subsequent discussion, we
explore the interpretation of these topographic pro
files in the context of the neuroanatomical networks
relating to motor control, as well as their potential
applicability in clinical research.
The metabolic anatomy of parkinsonism

In this study of PD, SSM analysis revealed a ma

jor covariance profile (Topographic Profile 1) that
was defined topographically by the key neuroana
tomical elements of the motor control system. This
profile was characterized by large positive region
weights for the lentiform nucleus, thalamus, pons,
and cerebellum and large negative region weights
for the lateral frontal, paracentral, and parietal as
sociation areas. The occipital cortex, a "neutral"
brain region uninvolved in the disease proces s
(Gibb, 1992), had region weights nearest zero and,
therefore, became a convenient reference point for
the other regional values. The region weights on
each topographic profile, multiplied by the associ
ated SSF, constitute the contribution of the profile
to overall normalized brain metabolism. Therefore,
the region weights for Topographic Profile 1 may be
interpreted as metabolic increases or decreases rel
ative to the occipital baseline.
The finding of increased metabolism in the lenti
form nucleus and thalamus in PD is consistent with
prior reports from experimental animal models of
4
parkinsonism. In e C]-2-deoxyglucose autoradio
graphic experiments, unilateral nigrostriatal lesions

793

THE METABOLIC TOPOGRAPHY OF PARKINSONISM

3
2

FIG. 3. Scatter diagram showing the SSFC1

scores in normals (0) and PO patients (. ) . M ean
values (SO) are displayed by vertical bars.
These values were significantly elevated in the
H&Y Stage I group. The discrimination line
(dashed) correctly identifies all H&Y Stage I pa
tients and 18 of 20 normals.

"l

u..,U

C/)
C/)

:1

.""" """"""" &

:
.

f:
(;

-1

-2

-3

------

Normal

give rise to increased rCMRglc in the ipsilateral

globus pallidus (Kozlowski and Marshall, 1980;
Wooten and Collins, 1981; Crossman et aI., 1985;
Palombo et aI., 1990; Mitchell et aI., 1992) . Meta
bolic change in the corpus striatum has been less
consistent, suggesting either unchanged (Wooten
and Collins, 1981; Mitchell et aI., 1992), decreased
(Kozlowski and Marshall, 1980; Schwartzmann
et aI., 1993), or increased (Palombo et aI., 1990)
rCMRglc on the lesioned side. Increased metabolism
in the ventral thalamus has been a consistent finding
(Kozlowski and Marshall, 1980; Crossman et aI.,
1985; Palombo et aI., 1990; Schwartzmann et aI.,
1993) . These findings have been considered as re
flecting the release of the basal ganglia from nigral
dopaminergic inhibition. Specifically, the loss of in
hibitory nigrostriatal dopaminergic projections re
sults in functional overaction of the putamen, with
a consequent increase in the firing of inhibitory af
ferents to the lateral pallidum. As rCMRglc is
determined primarily by afferent synaptic activity

Hoehn & Yahr Stage

II-V

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

lidal metabolism should increase. The reduction in
inhibitory afferents to the subthalamic nucleus
(STH) from the LGP results in decreased STH me
tabolism-in the face of increased neuronal activity
in that region. STH excitatory projections to the
medial pallidum (MGP) thereby increase, resulting
in increased MGP metabolism. Similarly, inhibitory
projections from the MGP to the ventral thalamus
also increase, resulting in increased metabolism in
these thalamic structures as well.
The striking regional abnormalities demonstrated
by autoradiography in experimental animal models
may be obscured in lower-resolution human PET
studies. A number of early PET studies demon
strated hemispheric asymmetries in basal ganglion
metabolism, with a bias toward metabolic increases
contralateral to the clinically more affected limbs
(Martin et aI., 1984; Wolfson et aI., 1985) . Localized
basal ganglion hypermetabolism in bilaterally af
fected individuals was not consistently evident in

18

en

15

"

C
0..
::l

0
u
U)
>
.....

'5
'0,
i:i:

12
FIG. 4. Correlations in PO patients be
tween UPORS rigidity ratings .and SSF1
scores. A significant positive correlation
(r = 0.62, P < 0.01) was found between
these two variables.

o +----=,-----,-----._--r_--_.
-1.00

-0.50

0.00

0.50

1.00

1.50

2.00

2.50

3.00

SSF,

J Cereb Blood Flow Metab, Vol. 14, No.5, 1994

794

D. EIDELBERG ET AL .
(A)
3

2
.

u.

en
en

0
(

-1

I
I

. - ......

- - - - - - - - - - _

. . . .

-2

-3
NORMAL

PO

(8)

3
FIG. 5. Scatter diagram showing the subject
scores for the three topographic profiles (A,
SSF1; 8, SSF2; and C, SSF3) identified in a combined-group SSM analysis of the 10 SND patients (A), 10 age- and severity-matched PD patients (_), and 10 age-matched normal subjects
(0). (See text.) M ean values (SD) are displayed
by vertical bars. The discrimination line
(dashed) based on SSF1 (A) correctly identifies
9 of 10 members of the SND group and 9 of 10
members o f the age- and severity-matched PD
group.

SNO

u.N

en
en

-1

-2

-3
NORMAL

PO

SNO

(C)

M
U.

en
en

c'

c'

-1

-2

-3
NORMAL

earlier PET studies (Kuhl et aI., 1984; Rougement et

aI., 1984) but has been reported using modern to
mographs of improved resolution (Blesa et al.,
1991).
J Cereb Blood Flow Metab, Vol. 14, No.5, 1994

PO

SNO

The inconsistencies in previous FDG/PET stud

ies may stem from inherent difficulty in extracting
quantitative measures of pallidal metabolism from
the larger lentiform ROI. Indeed, because of the

THE METABOLIC TOPOGRAPH Y OF PARKINSONISM

necessary spatial inclusion of the less consistently
affected putamen, pallidal hypermetabolism may
become obscured within the composite lentiform
regional measurement. Lentiform hypermetabolism
may therefore be low in absolute terms and may not
be detectable using conventional statistical method
ologies. Additionally, our inability to quantify pall
idal rCMRgic precisely may obscure possible clini
cal-metabolic relationships that might exist be
tween this measure and tremor (Perlmutter and
Raichle, 1985).
Apart from the inherent physical limitations of
PET in the measurement of rCMRgJc in small re
gions (Mazziotta et aI., 1981), PET datum analysis
requires statistical consideration of the mUltiplicity
of regional measurements compared between
groups (Winer, 1971). In this report we have treated
the individual rCMRg Jc and rCMRg Jc/GMR mea
sures as independent observations and have cor
rected the associated p values accordingly. In keep
ing with our earlier observations (Eidelberg et
aI., 1990), we found no significant differences in
rCMRgJc and rCMRg1c/GMR between the PD and
the normal groups and no significant clinical corre
lations with these variables, even without imple
menting the stringent Bonferroni correction. None
theless, we are cognizant of the effects of interre
gional covariation in PET data and have developed
SSM as a means of quantifying these regional inter
actions (Moeller et aI., 1987). SSM analysis thus
provides an alternative to traditional statistical ap
proaches for the identification of small biologically
relevant signals (Sackeim et aI., 1993). By delineat
ing independent topographic profiles, SSM tech
niques can extract covariate functional elements
within anatomically large and functionally hetero
geneous ROIs. We associate the covariate lentiform
and thalamic hyperfunction identified in Topo
graphic Profile 1 with the hypermetabolism of the
pallidum and ventral thalamus demonstrated in the
autoradiographic animal experiments.
In addition to the basal ganglion-thalamus inter
action, this topographic profile included abnormal
covariate interactions of the cerebellum and pons.
These two interconnected structures, with the thal
amus, constitute a separate motor control system
operating in parallel to the basal ganglion circuits
(Brodal, 1981). Indeed, these two systems share a
common output to the primary and supplementary
cortical motor areas. Although lesions of the pons
and cerebellum have not been demonstrated histo
pathologically in PD, these regions have been im
plicated in experimental rodent models of 1-methyl4-phenyl- l ,2,3 , 6-tetrahydropyridine neurotoxicity
(Takada et aI., 1993) . In addition, these regions may

795

be abnormally activated in the course of parkinso

nian tremor (Brooks et aI., 1992). Our data indicate
that subject scores for Topographic Profile 1 did not
correlate with resting-state 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 be
helpful in determining whether the pontocerebellar
hypometabolism evident in Topographic Profile 1 is
part of a discrete tremor-specific network or wheth
er it is a fragment of a more generalized disease
related pattern.
Both basal ganglion and cerebellar subcortical
motor systems exert their influence by modifying
the activity of the cortical motor areas. Indeed, To
pographic Profile 1 identified hypofunction of sev
eral cortical regions involved in motor control.
Nonetheless, primary, premotor, and supplemental
motor ROIs could not be accurately specified. Be
cause of intersubject variability in the cerebral con
volutions and their relationship to local cytoarchi
tecture (e.g., Le Gros Clark, 1945; Eidelberg and
Galaburda, 1984; Rademacher et aI., 1993), as well
as potential focal atrophy effects, deformations into
a common coordinate space (e.g., Fox et aI., 1988)
may be inherently imprecise, especially without in
dividual subject activation data. Three-dimensional
MRI/PET coregistration may be somewhat more re
liable for primary sensorimotor localization (e.g.,
Grafton et aI., 1991) but remains inexact for the
supplementary motor area (SMA), which is not con
sistently defined by sulcal markings. To preserve
correspondence with the regional information de
rived in our previous study, we opted for similarly
large ROIs. Comparison with standard anatomical
(Eycleshymer and Schoemaker, 1911), architec
tonic (von Economo, 1992), and functional stereo
tactic (Talairach and Tournoux, 1988) atlases re
veals the lateral frontal ROI to be composed largely
of elements of the lateral premotor cortex and the
frontal eye fields [areas 6 and 8 of Brodmann (von
Economo, 1929)]. [The pixel contribution of pri
mary sensorimotor cortex (area 4) to this ROI is
considered to be small (see Fig. lB).] Similarly, the
paracentral ROI included medial superior frontal re
gions corresponding largely to the SMA !,medial
area 6 or GFd (Talairach and Tournoux, 1988)] .
Thus, the reduced weights o f these regions noted in
Topographic Profile 1 is suggestive of diminished
activity of the lateral premotor regions and SMA.
Reductions in the activity of these regions are likely
to stem from overactive suppression of the ventral
thalamic nuclei caused by excessive MGP inhibi
tory outflow. As these cortical regions receive subJ Cereb Blood Flow Metab, Vol. 14, No.5, 1994

796

D . EIDELBERG ET AL .

stantial afferents from the ventral thalamus, sup

pression of these thalamic nuclei is apt to reduce the
metabolic activity of their motor cortical projection
targets. These findings are consistent with evidence
of reduced metabolism in premotor cortex in pri
mate models (Palombo et aI., 1990) and PET evi
dence of reduced activation of the SMA during the
performance of motor tasks in PD patients (Jenkins
et aI., 1992 ; Playford et aI., 1992).
The hemispheric contrast profiles contain many
of the regional elements included in Topographic
Profile 1 of the bihemispheric analysis. Both signif
icant contrast profiles reflect metabolic asymme
tries in the thalamus covarying with asymmetries in
other associated motor regions. We found that the
relationship of the thalamic asymmetries with the
other regional asymmetries was often of reciprocal
polarity, i.e., relative increases in thalamic metab
olism were associated with relative decreases in the
metabolism of the covariate region. For example, in
Contrast Profile 1 , thalamic asymmetries were as
sociated with SMA asymmetries of opposite polar
ity. This reciprocal relationship is consistent with
the opposite polarity of the region weights for the
two structures noted in Topographic Profile 1 of the
bihemispheric analysis. In Contrast Profile 2 , a neg
ative covariance was observed between caudate
and thalamolentiform asymmetries. This may mir
ror the findings of caudate and putamen hypome
tabolism associated with pallidal metabolic in
creases, as noted in several autoradiography studies
(Kozlowski and Marshall, 1980 ; Schwartzmann et
aI., 1 993).
The finding of parietal hypofunction is somewhat
surprising, as this region is not associated with mo
tor control systems. We interpret this finding to
suggest a second locus of pathology in the PD study
sample, involving brain regions implicated in the
Alzheimer disease process (e.g., Foster et aI., 1984 ;
Haxby et aI., 1985 ; Duara et aI., 1986). Given the
histopathological overlap between classical nigral
Lewy body changes and cortical neurofibrillary tan
gle pathology in postmortem specimens (Gibb,
1 992), it is reasonable that neocortical involvement
may impact upon the metabolic profiles of PD pa
tients, especially those with more advanced dis
ease. Indeed, hypometabolism of the parietal asso
ciation cortices has been reported in PD patients
with dementia (Kuhl et aI., 1984; Schapiro et aI. ,
1 993 ) . Our data suggest that these cortical changes
may be inseparable from the parkinsonian disease
process, as suggested by the high incidence of cog
nitive deterioration in the PD population (Mayeux
et aI., 1990). Further investigations comparing de
mented and nondemented PD patients with quantiJ

Cereb Blood Flow Metab, Vol. 14, No. 5, 1994

tative neurops ychological correlations will be

needed to elucidate the precise biological meaning
of these metabolic changes.
The topographies of the other significant profiles
extracted in this analysis have no immediate inter
pretation in the framework of neuroanatomical
pathways relating to motor control or the parkinso
nian disease process. Furthermore, these profiles
offered no simple regional reference point, such as
the occipital cortex in Topographic Profile 1, by
which to define topographic functional deviations.
The roles of these other profiles in defining the met
abolic topography of parkinsonism may be limited.
Nonetheless, they may reflect shared aspects of
brain function common to the different clinical
groups. For example, Topographic Profile 2 was
characterized by covarying topographic increases
in occipital and parietal function associated with de
creases in temporal lobe and midbrain function. Be
cause of the commonality of this profile to both
normal and disease populations, we associate this
profile with the eyes-open resting state. Similarly,
the relative hypofunction of the midbrain and me
dial temporal areas may reflect low activity of the
reticular and limbic attentional systems (Mesulam,
1981) in an unfocused non-task-driven resting state.
SSM may also identify topographic profiles
shared by different disease states. We found that
although PD and SND diverge in their representa
tion of Topographic Profile 1, these two phenome
nologically similar conditions may share other to
pographic features indicative of abnormal motor
system output. In this vein, it is of interest that
SSF3 values, which reflect varying degrees of pre
motor and supplementary motor hypofunction, may
be abnormally elevated in SND, with a trend to
ward elevation in severity-matched PD patients
(Fig. 5C). These results must be interpreted with
caution in that they fail to achieve significance with
the conservative Bonferroni correction for the three
SSFs compared. Nonetheless, the regional topogra
phy of this unrotated profile is neuroanatomically
relevant in that, like Topographic Profile 1, it also
reflects key elements of cortical motor output. This
suggests that the between-group differences in the
associated subject scores may not be due strictly to
chance. With this caveat, these findings imply that
SND and PD may effect their clinical manifesta
tions through a common mechanism: reduced func
tion of premotor and SMA cortical efferent projec
tions. Indeed, reduced activity in these cortical re
gions has been suggested as the functional basis for
the akinesia characterizing clinical parkinsonism
(e.g., Playford et aI., 1992 ; Watts and Mandir,
1992). Nonetheless, SMA and premotor hypofunc-

THE METABOLIC TOPOGRAPHY OF PARKINSONISM

tion may be the result of abnormalities in separate
neural systems in different forms of parkinsonism:
in PD, with primarily nigral dysfunction and lenti
form hypermetabolism, through an accentuation of
Topographic Profile 1; in SND, with primarily stri
atal dysfunction and lentiform hypometabolism,
through an accentuation of Topographic Profile 3.
Potential clinical applications

Disease Severity Assessment. We found that

SSF 1 scores correlated significantly with H&Y
scores and composite motor UPDRS ratings of
overall disease severity, as well as with individual
UPDRS ratings for rigidity and bradykinesia. The
significance of these findings must be interpreted in
the context of the mUltiple correlations performed
between each of the seven clinical measures and
numerous regional metabolic measures. Because of
the close relationship between the overall severity
ratings and the individual bradykinesia, rigidity,
and gait ratings, these scores could not be consid
ered as independent observations in the clinical
metabolic correlations which were performed. We
therefore chose to correct the significance levels of
these correlations for the two major independent
subsets of clinical scores within the motor UPDRS
(i. e . , bradykinesia, rigidity, and gait scores vs.
tremor scores) . As in our earlier report (Eidelberg
et aI. , 1990), none of the clinical correlations with
the many rCMRg lc and rCMRglc/GMR measures
achieved significance-even without the Bonfer
roni correction. This contrasts with the clinical
metabolic correlations of SSF I' Correlations of this
parameter with H&Y scores, composite motor
scores, and individual bradykinesia and rigidity
scores were all significant, even with a stringent
correction for multiple regional comparisons, and
2
were all of a similar magnitude (R - 30%) . These
significant clinical-metabolic correlations suggest
that the metabolic contribution of this abnormal
brain topography increases with advancing clinical
disability. These results also indicate that SSF 1 val
ues correlate with quantitative clinical disability
with an accuracy comparable or superior to that of
striatal FDOPA uptake rate constants (Eidelberg et
aI. , 1990; Takikawa et aI. , 1994) . Because of the
close intrasubject correlation between SSF 1 values
and striatal FDOPA uptake rate constants (Eidel
berg et aI., 1990), SSF1 calculation may provide a
practical, though indirect, measure of nigrostriatal
dysfunction applicable to certain clinical research
situations. We have demonstrated previously that
SSM techniques may be applied to individual pa
tient FDG/PET data to calculate the subject score
for a predetermined topographic profile (Moeller

797

and Strother, 1991) . Moreover, SSM may be ap

plied to sets of metabolic data acquired at different
times in the course of disease to gauge progression
and the effects of treatment. Thus, calculating SSF 1
values in PD patients studied longitudinally with
FDG/PET can provide an additional independent
metabolic measure of disease progression beyond
the quantitative clinical examination. Indeed, an ac
cessible metabolic parameter such as SSF 1 may be
a 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 compara
tive study will be needed to assess the relative
merits of these two PET methods as potential mark
ers of the parkinsonian disease process.
Early Diagnosis and Preclinical Detection . Al
though the major topographic profile extracted from
the analysis of bihemispheric rCMRglc data differ
entiated the PD group from age-matched normals,
its discriminative value is limited to PD2 patients in
whom the clinical diagnosis is generally obvious.
SSF 1 was not different in the normal and PD1 sub
groups and did not discriminate those patients for
whom differentiation from normal is clinically rele
vant. Nonetheless, our data demonstrate the poten
tial applicability of the topographic contrast profiles
in discriminating the mildest patients (H& Y Stage I)
from normals. We found that the SSFc l scores cor
rectly classified all five H&Y I patients, while mis
classifying only 2 of 20 normals (Fig. 3 ) . This degree
of discrimination is comparable to that achieved
with FDOPA/PET (Brooks et aI. , 1990; Takikawa et
aI. , 1994), suggesting the applicability of SSF cl mea
surements in mildly affected patients in whom the
clinical diagnosis is uncertain. In contrast to the
H&Y I patients, the more advanced patients were
not accurately discriminated from normals by S S Fc l
measures. Nonetheless, these patients are generally
easily identified clinically and are not apt to be con
fused with normals. Indeed, SSF 1 measures from
bihemispheric rCMRglc analysis may be more suit
able for identifying advanced patients if additional
metabolic data are needed to support the clinical
diagnosis.
The topographic contrast profiles depict covary
ing metabolic asymmetries of a small ma.gnitude
that underlie the clinical motor asymmetry charac
teristic of the early parkinsonian state. We found
that the topographic representation of these asym
metries includes fragments of the abnormal bilateral
profile, involving primarily the lentiform nucleus,
thalamus, and paracentral cortex. Additionally, the
contrast profile that discriminated patients with
early disease was reproducible in the prior dataset.
J

Cereb Blood Flow Metab, Vol. 14, No. 5, 1994

798

D . EIDELBERG ET AL .

These topographic contrast profiles quantify inher

ent metabolic asymmetries , which like clinical
asymmetries, are evident in the earliest symptom
atic stages of the illness (Hoehn and Yahr, 1967). It
appears that relative lentiform hypermetabolism ap
pears first contralateral to the involved hemiparkin
sonian limbs, ipsilateral to the striatum, with the
greater degree of presynaptic nigrostriatal dopami
nergic dysfunction (Eidelberg et aI., 1990). As nigral
degeneration progresses and generalizes, the dopa
minergic functioning of the opposite side also de
creases, resulting in bilateral clinical involvement
and concomitant bilateral metabolic changes. Thus,
with the development of clinical parkinsonism, a
metabolic transition appears to occur between a
state of normal symmetry and a state of pathologi
cal clinical and metabolic asymmetry. Contrast pro
file descriptors such as SSFc 1 may therefore have
utility in delineating this transition. Moreover,
SSFcl calculation in individual cases may have clin
ical value in confirming the diagnosis of PD in
mildly affected asymmetrical patients. Addition
ally, to the extent that the nigral cell loss is likely to
be somewhat asymmetrical over the period of time
anteceding clinical symptoms, SSFc l might have
value in the preclinical identification of individuals
at risk for PD on genetic or environmental grounds.
Therefore, SSFC I values may provide a useful alter
native to traditional FDOPA/PET methods in this
regard (Brooks, 1991; Sawle, 1993). The realistic
clinical utility of the contrast profiles in early diag
nosis and preclinical detection can be ascertained
only through the study of more early involved pa
tients and preclinical cohorts.
Differential Diagnosis . It is known that up to 25%
of patients clinically diagnosed in life with PD have
evidence of other degenerative disorders at post
mortem evaluation (Rajput, 1984; Gibb, 1992). Al
though these other conditions are pathologically
heterogeneous and some are identifiable on clinical
grounds by characteristic neurological signs, they
are often indistinguishable from each other as well
as from PD. We have used quantitative FDG/PET
to characterize and differentiate some of these dis
orders (Eidelberg et aI. , 1991, 1993; Eidelberg ,
1992; Przedborski et aI., 1993). SND represents the
akinetic-rigid disorder clinically most like PD, ac
counting for 10% of the parkinsonian disorders ex
amined at postmortem (Gibb, 1992). Because SSM
analyses are performed on combined clinical sam
ples and are blind to patient class designations, we
sought to utilize this method to explore its potential
application in the differential diagnosis of clinically
similar (but presumably pathologically different)
neurological conditions. In the current investigation
J

Cereb Blood Flow Metab. Vol. 14, No.5, 1994

we used the SND population to address the follow

ing questions relating to the use of SSM descriptors
in differential diagnosis: (a) Did the inclusion of a
third clinically discrete cohort into the SSM analy
sis introduce a new topographic profile not evident
in the original two-group analysis? (b) Did the in
clusion of the third group alter the metabolic topog
raphy of the profiles extracted from the original
two-group analysis? and (c) Did any of the SSM
descriptors discriminate individual SND patients
from their severity-matched PD counterparts with
sufficient accuracy to be useful as an imaging ad
junct to the clinical examination?
1 33
In a
Xe perfusion study of mood disorder pa
tients, Sackeim et aI. (1993) demonstrated that the
inclusion of a AD cohort, with a distinctly different
pathology, may introduce additional topographic
profiles related specifically to the newly included
disease type. Moreover, patients in the added co
hort had altered representations of the other topo
graphic profiles. In contrast, we found that the in
clusion of SND patients in the SSM analysis did not
create a novel SND-specific covariance profile. Our
findings also indicate that the topographies of the
three major covariance profiles were not altered by
the inclusion of SND patients. Rather, SND and PD
shared a common topographic space and differed
only in topographic profile scale and orientation
(i.e., SSF magnitude and sign). As expected from
prior reports on lentiform hypometabolism in SND
(DeVolder et aI., 1989; Eidelberg et aI., 1993), the
mean SSF 1 for this group was negative and lower
than in the PD group (Fig. 5A). We interpret these
findings to suggest that SSF 1 elevations are indica
tive of primarily nigral dysfunction (PD) , while
SSF 1 reductions reflect predominantly striatal dys
function (SND).
We found that in individual patients SSF 1 con
firmed the clinical diagnosis in 9 of 10 presumed
SND patients and 9 of 10 age- and severity-matched
clinical PD patients. Because the clinical differenti
ation of the parkinsonian movement disorders is in
herently imprecise, other methods of distinguishing
these patients may serve as useful adjuncts to the
clinical examination. Our findings suggest that SSM
calculations of SSF 1 from individual FDG/PET
scans may have sufficient sensitivity to enhance the
accuracy of the differential diagnosis of PD and
SND made solely on clinical grounds. Nonetheless,
the sensitivity of SSF 1 in discriminating these clin
ically similar conditions was only minimaily supe
rior to that of normalized striatal rCMRglc values or
18
F count rates (Eidelberg et aI., 1993). However,
differentiations based upon PET measurements in
single brain regions may be complicated by poten-

THE METABOLIC TOPOGRAPHY OF PARKINSONISM

tial observer bias and partial volume effects (Mazzi
oUa et aI., 1981). In contrast, the use of topographic
covariation profiles involving metabolic informa
tion from multiple brain regions may minimize such
errors. It should be noted, however, that because
metabolic changes are associated with clinical pro
gression in both groups, such diagnostic algorithms
require control groups strictly matched for disease
severity, age, and pharmacologic status. Further
studies with longitudinal comparisons and postmor
tem pathological confirmation are needed to ascer
tain the full diagnostic potential of this technique in
relation to the clinical examination.
Conclusions

In this work we demonstrate the utility of quan

titative FDG/PET methods in identifying abnormal
brain topographic profiles in PD and related disor
ders. These topographic profiles conform to known
anatomical systems associated with locomotion and
to regional metabolic data from experimental ani
mals models of parkinsonism. We have also dem
onstrated the reproducibility of these profiles
across populations and instrumentation.
Apart from their relevance to the understanding
of the metabolic organization of parkinsonism,
these topographic profiles have potential clinical
applicability in differential diagnosis and objective
disease assessment. Our results suggest further ap
plications for early diagnosis and preclinical detec
tion. Presently, dynamic FDOPA/PET methods
serve as the best-characterized tools for addressing
these clinical-research issues (Brooks et aI., 1991;
Eidelberg, 1992; Sawle, 1993). However, because
of technical difficulties in implementing these meth
ods, very few centers can undertake quantitative
FDOPA/PET imaging on a regular basis. In con
trast, FDG/PET methods are technically easier to
implement in most centers and may afford compa
rable data. Furthermore, to the extent that metab
olism is coupled to perfusion in these disorders (Ot
suka et aI., 1991) , analogous SSM approaches may
be applicable to regional cerebral blood flow map
ping with other imaging modalities such as single
photon emission CT and functional MRI.
Acknowledgment: This work was supported by grants
from the Parkinson Disease Foundation and the Dystonia
Medical Research Foundation. D.E. is a faculty fellow of
the Parkinson Disease Foundation and the United Parkin
son Foundation. S.T. is a Veola T. Kerr fellow of the
Parkinson Disease Foundation. We thank Dr. Abdel
Belakhlef, Mr. Claude Margouleff, and Ms. Janie Dill for
help with the PET studies , Dr. Robert Dahl and Mr.
Ralph Matacchieri for cyclotron support, and M s . Debra
Segal for manuscript preparation. We are grateful to Pro
fessor Harold A. Sackeim , Dr. Martin Lesser, and Dr.

799

Francine Mandel for their helpful comments. We ac

knowledge Dr. David A. Rottenberg' s important contri
bution to the earlier PET studies (Eidelberg et ai., 1990)
and thank him for providing those data to us for statistical
comparison.
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