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Differing patterns of striatal 18F-dopa uptake in Parkinson's disease multiple system atrophy and progressive supranuclear palsy.

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Dfiering Patterns of Striatal IsF-Dopa
Uptake in Parhnson's Disease, Multiple
System Atrophy, and Progressive
Supranuclear Palsy
D. J. Brooks, MD,*-I-V. Ibanez, MD," G. V. Sawle, MRCP,* N. Quinn, MD,? A. J. Lees, MD,I
C. J. Mathias, MD,? R. Bannister, MD,? C. D. Marsden, FRS,t and R. S. J. Frackowiak, MD't
Using positron emission tomography (PET), we studied regional striatal **F-dopauptake in 16 patients with L-doparesponsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive
supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD
showed significantly reduced mean uptake of "F-dopa in the caudate and putamen compared to controls, but while
function in the posterior part of the putarnen was severely impaired (455%of normal), function in the anterior part of
the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean '*F-dopa uptake in the posterior
putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive
supranuclear palsy showed equally severe impairment of mean "F-dopa uptake in the anterior and posterior putamen.
Caudate 18F-dopauptake was also significantly lower in patients with progressive supranuclear palsy than in patients
with PD, being depressed to the same level as that in the putarnen. Mean "F-dopa uptake values in the anterior
putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy
levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in
striatal "F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude
that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic
function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in
multiple system atrophy and progressive supranuclear palsy. If an kinetic-rigid patient has equally depressed '*F-dopa
uptake in the caudate and putamen, that person is likely to have neuropathological changes other than those of
idiopathic PD.
Brooks DJ, Ibanez V, Sawle GV, Quinn N, Lees AJ, Mathias CJ, Bannister R, Marsden CD,
Frackowiak RSJ. Differing patterns of striatal I8F-dopa uptake in Parkinson's disease, multiple
system atrophy, and progressive supranuclear palsy. Ann Neurol 1990;28:547-555
Parkinson's disease (PD), multiple system atrophy
(MSA), and progressive supranuclear palsy (PSP)also known as Steele-Richardson-Olszewskisyndrome
-are pathologically distinct alunetic-rigid syndromes.
In PD Lewy body degeneration of the pigmented and
other brainstem nuclei is present 111. In MSA, which
includes striatonigral degeneration, olivopontocerebellar degeneration, and the Shy-Drager syndrome in its
spectrum, there is degeneration in the absence of inclusion bodies of the basal ganglia, pontine nuclei,
olives, cerebellar Purkinje cells, and intermediolateral
columns of the cord [Z-41. The pathology of PSP is
characterized by the formation of neurofibrillary tangles and degeneration of the basal ganglia and brain-
stem nuclei [ S , 61. In P D there is severe loss of dopamine and noradrenaline in the caudate and putamen,
while striatal choline acetyltransferase (CAT) and glutamate decarboxylase (GAD) levels are preserved [7).
In MSA and PSP, striatal levels of dopamine, noradrenaline, CAT, and GAD are all depressed {2, 7-91.
In spite of the clear pathological differences between PD, MSA, and PSP, these three akinetic-rigid
syndromes can cause diagnostic difficulties in their
early clinical stages [10-12}. All three conditions may
be L-dopa responsive initially, and resting tremor,
though less common than in PD, can occur in patients
with MSA and PSP. Patients with PSP generally have a
symmetrical akinetic-rigid syndrome with predomi-
From the Medical Research Council "Cyclotron Unit, Harnmcrsmith Hospital, and the ?Institute of Neurology, Queen Square,
London, United Kingdom.
Received Jan 29, 1990, and in revised form Apr 25. Accepted for
publication Apr 30, 1990.
Address correspondence to Dr Brooks, MRC Cyclotron Unit,
Hammersmith Hospital, DuCane Road, London W12 OHS, UK.
Copyright 6 1990 by the American Neurological Association
547
Table 1. Clinical Details of the Patients with L-Dopa-Responsive ParkinJon? Disease
~~
Patient No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Sex
M
M
M
M
M
M
F
M
F
F
F
M
M
M
M
F
Age
(yr)
63
44
63
57
47
55
64
70
55
48
70
53
39
41
58
76
Duration
(yr)
10
3
15
10
11
3
7
6
15
15
0.5
9
3
4
4
1.5
Hoehn and
Yahr Score
3
2
3
3
3
3
3
4
4
4
2
3
1
2
1
2
nantly increased axial tone, a bulbar palsy, and neck
extensor rigidity, but these features are not diagnostic.
The characteristic supranuclear downgaze palsy of PSP
may be a late clinical finding [123, and on occasion can
be found in MSA {13}, multi-infarct disease {14},
Creutzfeldt-Jakob disease [ 151, corticobasal degeneration [16}, and cortical Lewy body disease {171. PD and
MSA are both associated with autonomic failure [18).
Impairment of memory, and poor performance on
tests sensitive to frontal lobe function occur in both
PSP and PD [19). It has been estimated that up to
18% of patients thought to have idiopathic PD based
on clinical criteria prove to have other diagnoses at
autopsy [lo}. Recent series have suggested that MSA
and PSP constitute 5 to 1196, and 49% of cases of
parkinsonism, respectively [lo, 20). Clearly it would
be useful to have additional means of distinguishing
between akinetic-rigid syndromes in vivo. This would
aid clinical diagnosis, and also provide homogeneous
patient populations for evaluation of treatment regimes.
The purpose of this study was to examine patterns
of disruption of the presynaptic dopaminergic function
in the caudate, and anterior and posterior parts
of the putamen, using the positron emission tomography (PET) tracer 18F-6-fluorodopa(I8F-dopa), to see
whether differences were evident between patients
clinically diagnosed as having probable idiopathic PD,
MSA, or PSP. 18F-Dopa is taken up and retained by
the caudate and putamen, a proportion being converted to "F-dopamine [21). The striatal lSF signal
after administration of this tracer thus provides information about the functional integrity of nigrostriatal
dopaminergic neurons. We were also interested to see
548
Annals of Neurology
Vol 28 N o 4
October 1990
Treatment
L-Dopa, amantadine
Deprenyl, amantadine
L-Dopa, benzhexol
L-Dopa, bromocryptine
L-Dopa, orphenadrine, bromocriptine
L-Dopa
Benzhexol
L-Dopa, deprenyl
L-Dopa, orphenadrine, bromocriptine
L-Dopa, bromocriptine
Nil
L-Dopa, benzhexol, deprenyl
Propranolol
Nil
L-Dopa, deprenyl
L-Dopa
whether a decline in 18F-dopa uptake in the putamen
and caudate correlated with locomotor disability in
PD, MSA, and PSP. In this way we hoped to demonstrate distinct patterns of nigral involvement in PD,
MSA, and PSP, and to determine the dependence of
locomotor function in PD, MSA, and PSP, on the integrity of the nigrostriatal dopaminergic pathways.
Materials and Methods
Patient Selection
Sixteen patients with probable idiopathic PD were scanned
by PET. All had an L-dopa-responsive, akinetic-rigid syndrome, without evidence of a supranuclear gaze palsy, cerebellar ataxia, or pyramidal signs. Computed tomography
(CT) brain scans showed no significant abnormalities. Their
age range was 39 to 76 years (56 5 11 years); clinical disease
duration, 6 months to 15 years (9.2 2 5.1 years); and
locomotor disability (assessed after 12 hours without medication) ranged from l to 4 on the Hoehn and Yahr scale [22].
Details on individual patients with P D are shown in Table 1.
The 18 patients with MSA had poorly or non-L-doparesponsive, akinetic-rigid syndromes. Fifteen had impaired
cardiovascular reflexes due to autonomic failure, and 10 had
cerebellar ataxia. None had evidence of a supranuclear gaze
palsy or dementia. In 9 patients, CT and/or 0.15-Tesla magnetic resonance imaging (MRI) bran scans were normal,
whereas the other 9 showed evidence of cerebellar and
brainstem atrophy. The age range was 40 to 68 years (56 t
9 years), duration of locomotor problems was 1 to 10 years
(4.1 2 3.0 years), and locomotor disability ranged from 2 to
5 on the Hoehn and Yahr scale when assessed after 12 hours
without medication. Details on individual patients with MSA
are given in Table 2.
The 10 patients with PSP all had a poorly or non-L-doparesponsive, symmetrical akinetic-rigid syndrome with dominant axial rigidity, evidence of a supranuclear downgaze palsy
Table 2. Details of the Putients with Multiple System Atrophy
Patient
No.
Sex
Age
(yr)
Parkinsonism
Duration (yr)
17
18
19
20
F
M
F
M
53
67
40
52
10
3
21
22
M
F
64
55
23
24
M
M
53
58
4
25
26
27
28
67
61
29
30
M
M
M
F
M
M
68
43
67
2
10
5
5
10
31
32
33
34
M
M
M
F
55
59
42
61
54
4
3
1
6
3
4
Hoehn and
Yahr Score
Autonomic
Failure
Cerebellar
Ataxia
MRIiCT
3
5
3
4
Yes
Yes
Yes
No
Yes
Yes
No
No
CA
CBA
N
N
2
4
Yes
Yes
Yes
Yes
CA
CBA
None
Poor
4
3
Yes
Yes
Yes
Yes
BA
N
NT
None
3
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
No
No
CA
N
CA
CBA
NT
None
Poor
NT
Poor
None
Yes
Yes
No
No
Yes
No
No
No
4
4
3
2
2
4
4
4
2
1
1
3
5
N
N
GA
N
N
N
L-Dopa
Response
NT
NT
Poor
Poor
Poor
Poor
None
None
Treatment
FC
FC
None
L-Dopa, deprenyl,
bromocryptine
L-Dopa
L-Dopa, TC, oxybutynin
FC
L-Dopa, bromocryptine
FC
Benzhexol
L-Dopa
FC
None
L-Dopa, amantadine
L-Dopa, terodilene
L-Dopa, TC
L-Dopa
L-Dopa
= cerebellar atrophy; BA = brainstem atrophy; CBA = cerebellar and brainstem atrophy; GA = general atrophy; N = normal; NT =
not tested due to severe orthostatic hypotension; FC: = fludrocortisone; TC = tricyclic antidepressant.
CA
andlor absent vertical optokinetic nystagmus, and 9 had a
striatal pseudobulbar palsy. Evidence of dementia with or
without cortical release signs was present in 8 of 10 patients.
Two patients were impotent, but none had significantly impaired cardiovascular reflexes. Their ages ranged from 62 to
75 years (68 2 4 years); clinical disease duration, 6 months
to 8 years (3.5 t- 2.2 years); and locomotor disability ranged
from 2 to 5 on the Hoehn and Yahr scale when assessed
after 12 hours without medication. S i x had CT scans that
were normal, 3 had evidence of mild generalized cortical
atrophy, and 1 had evidence of cerebellar and brainstem
atrophy. Details on individual patients with PSP are shown in
Table 3.
Results were compared with 30 normal volunteers with an
age range of 30 to 77 years (63 i 10 years). None had
evidence of clinical disability on neurological examination.
All subjects gave written informed consent prior to PET
scanning. Permission to perform these studies was obtained
from the Ethics Committee of the Hammersmith Hospital,
London, United Kingdom, and from the Administration of
Radioactive Substances Advisory Committee, United Kingdom.
Scanning Procedzlre
PET scans were performed using the CTI 981/08/12 tamograph (CTI, Knoxville, TN) yielding 15 simultaneous planes
with an axial full-width-half-maximum resolution of 7 mm
and an inplane resolution of 8.5 mm x 8.5 mm [23].Correction for tissue attenuation of 51 1-keV gamma radiation was
measured with an external "Ge ring. If patients were taking
antiparkinsonian medication, this was stopped 12 hours prior
to PET. One hour before being scanned, patients were given
a 100-mg oral dose of carbidopa, a peripheral decarboxylase
blocker. All subjects were fasted for 12 hours before their
study.
Two to 5 mCi of "F-dopa (mean specific activity, 8 mBq/
pmol) in 10 ml of normal saline solution was infused intravenously over 2 minutes. Scanning began at the start of the
tracer infusion with serial I-minute, increasing to 5-minute,
time frames to provide 24 time frames over 90 minutes.
Data Analysis
Region-of-interest (ROI) analysis was performed on SUN
3/60 workstations (Sun Microsystems, Silicon Valley, CA)
using image analysis software (ANALYZE 2.0, BRU, Mayo
Foundation, Baltimore, MD). In all subjects the positions of
striatal and occipital structures were defined by summing
time frames, to create an integrated image representing activity collectcd 60 to 90 minutes after "F-dopa administration.
ROIs were placed by inspection, and their coordinates were
confirmed by reference to the stereotactic atlas of Talairach
and colleagues [24]. Where patient striatal ROIs were difficult to define by inspection, their positions were checked by
superimposing CT and MRI images at the appropriate axial
level over PET images. ROIs were defined in a standard
arrangement: one circular region with a diameter of 8.2 mm
was placed on the head of caudate, and three circular regions with a diameter of 8.2 mm were lined along the axis of
Brooks et al: '*F-Dopa Uptake in Parkinsonian Syndromes
549
Table 3. Details of the Patients with Progressive Supranuclear Palsy
Patient
No.
Age
(yr)
35
36
37
38
39
40
75
68
66
67
66
62
41
Sex
Hoehn and
Yahr Score
Clinical
Duration
(yr)
3
5
4
3
0.5
2
4
4
71
M
M
M
M
M
M
M
3
3
3
8
5
42
68
M
3
5
43
44
63
74
M
M
2
3
1
1.5
4
SDP
Full
Full
Full
Full
Full
Full
Partial;
no OKN
Partial;
no OKN
Full
Partial;
no OKi'i'
Bulbar
Palsy
Axial
Rigidity
+
++
+
+
+
+
++
++
++
++
++
+
+
+
+
++
+
-
+
+
Dementia
CTiMRI
Treatment
C
C
C
M
C
P
M
N
N
N
CBA
GA
N
N
Nil
L-Dopa
L-Dopa
L-Dopa
Nil
Amitriptyline
L-Dopa
Nil
GA
M
Nil
GA
N
L-Dopa deprenyl
Nil
L-Dopa
SDP = supranuclear downgaze palsy; OKN = vertical optokinetic nystagmus; GA = generalized atrophy; CBA
atrophy; N = normal; M = impaired memory; C = frontal release signs; P = personality change.
the putamen for each hemisphere in both normal subjects
and patients. One circular region with a diameter of 32.8 mm
was placed over the occipital lobe of each hemisphere. This
array of ROIs was defined on the integrated images of the
two optimum, contiguous 7-mm planes, and then was superimposed on individual time frames. Averaged values for each
anatomical structure over two planes were then calculated
from the individual hemispheric ROI data.
Following correction for decay, regional time activity
cunres were plotted and specific striatal "F-dopa uptake was
analyzed using the multiple time graphical analysis (MTGA)
approach developed by Patlak and Blasberg [25], but with an
occipital rather than an arterial plasma input function. The
use of a tissue reference, rather than a plasma, input function
has been validated previously [26, 271. The MTGA approach effectively linearizes striatal 18F-dopa uptake curves
over 30 to 90 minutes of real time, and the gradients of
striatal 18F-dopa uptake curves obtained with this approach
can be regarded as influx constants, Ki min-l, which reflect
the rate of suiad "F-dopa uptake and storage as 18F-dopamine and its metabolites. Examples of typical MTGA curves
representing I8F-dopa uptake in the putamen are shown for a
normal subject and a patient with PSP in Figure 1.
Results
Figure 2 shows PET images of striatal "F-dopa uptake
at two axial tomographic levels, collected 60 to 90
minutes after intravenous administration of the tracer,
for a normal subject and patients with stage I11 PD or
PSP. It can be seen that caudate function was relatively
preserved in the patient with PD, but putamen tracer
uptake was significantly impaired. By contrast the images of the patient with PSP show uniform impairment
of striatal tracer uptake, the caudate and putamen being equally severely affected.
Figure 3 shows individual whole putamen, caudate,
and caudate minus putamen "F-dopa Ki values for the
550 Annals of Neurology Vol 28 No 4 October 1990
=
cerebellaribrainstem
Putamen 18F-Dopa uptake
putamen
occlpui
25
15
10
20
40
60
80
100
I occipital/occipital
120
140
(rnins)
Fig 1.A multiple time graphical analysis plot shwing the ratio
of putamen-occipital "F-dopa uptake against the expanded time
scaie integrated occipitalloccipital counts. Such plots are linear
between 30 and 90 minutes of real time, and their gradients
yield influx constants Ki min - I , rejecting striatal "F-dopamine
formation and storage.
control subjects and the patients. The mean whole
putamen, head of caudate, and caudate minus putamen
lsF-dopa IQ values are summarized in Table 4A. Mean
whole putamen tracer uptake was depressed to a similar level (=40% of normal) in PD, MSA, and PSP.
Caudate "F-dopa uptake was also significantly depressed in each of the three kinetic-rigid syndromes.
While caudate tracer uptake was reduced to the same
level as putamen uptake in PSP, the mean caudateputamen difference being close to zero, there was
significant sparing of caudate function in PD, 12 of the
16 patients with PD having normal levels of caudate
18F-dopa uptake. The mean caudate value in MSA fell
between the PD and PSP values; in some patients with
MSA the pattern resembled the PD pattern of relative
Putamen 18F-Dopa uptake in Parkinsonism
4
K i min
0 012
]
PDI161
MSA(18)
PSP(10)
0.008
0
O O C J
A
Caudate 18F-Dopa uptake In Parkinsonism
Nor (30)
0.01 0
-
B
MSA (18)
PD(161
t i F
PSP (10)
E
Fig 2. Integrated PET images of striatal "F-dopa uptake at two
axial levels for control subjects, patients with PD, and patients
with progressiie supranuclearpalsy (PSP), collected 60 to 90
minutes after infusion of tracer. I t can be seen that the head of
caudate is relatively preserved in PD, but the putamen and ventral striatal uptake is impaired. The striatum is globally aflected
in FSP. (Red represents high, and blue represents low activity on
the color scale.)
0.005-
i
0
0
o.co0
B
0
0
f
J
0
Caudate-Putamen 18F-Dopa uptake
Ki min
1
0'0101 PD(16J
0
0
sparing of caudate function, while others had the PSP
pattern of a similar degree of putamen and caudate
involvement. Table 4B summarizes mean anterior and
posterior putamen 18F-dopa Ki values for all patients.
Tracer uptake was depressed to similar levels in the
posterior putamen of all three groups of akinetic-rigid
patients. The anterior putamen was as severely involved as the posterior putamen in PSP, but there was
significant sparing of the anterior putamen in PD.
Mean tracer uptake in the anterior putamen in the
patients with MSA fell between PD and PSP levels.
Figure 4 shows individual caudate and putamen "Fdopa Ki values plotted against locomotor disability
measured on the Hoehn and Yahr scale for the patients with PD. As shown by both one-way analysis of
variance (ANOVA) and nonparametric Kendall rank
correlation ( T ) statistics, there was a significant inverse
correlation between putamen and caudate "F-dopa Ki
values and the degree of locomotor impairment. Similar plots are shown for patients with MSA and those
with PSP in Figures 5 and 6. As for PD, the patients
with MSA showed a significant inverse correlation between putamen and caudate "F-dopa uptake and locomotor disability using ANOVA statistics, though
only putamen I 6 values correlated inversely with
Hoehn and Yahr scores using Kendall rank correlation
statistics. The patients with PSP showed no correlation
between striatal "F-dopa uptake and locomotor function, and none of the akinetic-rigid groups showed any
0.005
-
0.000
i
n
MSA (18)
T:
PSP (10)
I
Nor (30)
1
0
0
-0.005
Fig 3. Scatter diagrams showing individual (A)putamen, {B)
caudate, and (C) caudate minus putamen "F-dopa K i values far
the normal subjects, patients with PD, patients with mult@e
system atrophy (MSA), and patients with progressive supranuclear palsy (PSP).
correlation between duration of clinical disease and integrity of their nigrostriatal dopaminergic systems.
Discussion
Inspection of Table 4A shows that mean whole putamen I8F-dopa influx constants were reduced to 37% to
48% of normal levels in the PD, MSA, and PSP
groups. This contrasts with putamen levels of dopamine measured in subjects at postmortem, which are
reduced to 10% or less of normal levels in PD and
MSA 12, 7, 281, and below 25% of normal levels in
PSP [8,9}. Endogenous striatal dopamine levels reflect
tyrosine hydroxylase activity, which is also reduced to
levels of 10% or less of normal in postmortem PD and
MSA striatum 12, 291. By contrast, specific striatal
"F-dopa uptake primarily reflects aromatic amino acid
Brooks et ai: '*F-Dopa Uptake in Parkinsonian Syndromes 551
Table 4. “F-Dopa Uptake in Akinetic-Rigid Syndromes (Ki min-
I)
A. Mean Striatal Values
Controls (30)
PD (16)
MSA (18)
PSP (10)
Caudate“
Putamen”
Cau-Puta
0.0107 ? 0.0019
0.0090 0.0021b
0.0073 -c 0.002Ib9‘
0.0051 -t 0.0018b,d
0.0098 2 0.0011
0.0047 ? O.OOIOb
0.0040 0.0017b
0.0036 ? 0.0020b
0.0009 2 0.0018
0.0043 f O.OOIOb
0.0033 ? 0.0019b
0,0010 -t 0.0019
Putamen (Anterior)”
Putamen Posteriora
*
*
B. Mean Regional Putamen Values
Putamen (Whole)”
Controls (30)
PD (16)
MSA (18)
PSP (10)
0.0098
0.0047
0.0040
* 0.0011
? O.OOIOb
* 0.0017b
0.0036
?
* 0.0017
0.0013b,e
* 0.0027b
*
*
0.0086
0.0039 ?
0.0036
0.0036 ?
0.0105 0.0021
0.0065 0.0015b
0.0050 t 0.0022b
0.0020h
0.0049
?
0.0019b
0.0020b
“Mean 2 standard deviation.
“p < 0.05 compared to normal (Bonferroni statistics).
cp < 0.025 compared to PD (Student’s t statistics).
< 0.001 compared to PD (Student‘s t statistics).
‘p < 0.05 compared to anterior putamen (Bonferroni statistics).
PD
=
Parkinson’s disease, MSA
=
multiple system atrophy, PSP
=
progressive supranuclear palsy.
MSA caudate 18F-Dopa uptake vs disability
PD caudate 18F-Dopa uptake vs disability
Ki min
Ki min
1
0.015
1
0.010
Q
0.005
a
a
7=.48
r=65
0 000
I
1
3
2
0
4
.
0
0
k.50
2
T=.18
0
3
-
1
4
,
5
HIY
A
Ki min
-‘
On*
MSA putamen 18F-Dopa uptake vs disability
PD putamen 18F-Dopa uptake vs disability
Ki min
-1
0.008
1
1
0.004
0 004
Q
k.47
T=.37
k56
0 000
Q
7=.40
I
1
3
2
4
5
HIY
B
Fig 4. Plots of individual total (A)caudate and (3)putamen
“F-dopa Ki values against locomotor disability for patients with
PD. Significant negative correlations were found: ANOVA--p
< 0.025 putamen, p < 0.005 caudate; Kendall-p < 0.05
putamen, p < 0.01 caudate.
552 Annals of Neurology
Vol 28 N o 4
October 1990
Fig 5 . Plots of individual total (A) caudate and (B) putamen
“F-dopa Ki values against locomotor disability for patients with
multiple system atrophy (MSA).Significant negative correlations
were found: ANOVA--p < 0.05 putamen, p < 0.05 caudate;
Kendull--p < 0.05 putamen, p = 0.18 (not significant) caudate.
PSP caudate 18F-Dopa uptake vs disability
1
Ki min
oolol
I
Q
Q
0.005
0
T=.O8
r=.02
A
PSP putamen 18F-Dopa uptake vs disability
Q
Q
0.004
1
B
0
I
r-23
T=.29
0.000
1
1
2
3
4
5
HLY
B
Fig 6. PLts of individual total (A) caardate and (B)putamen
"F-dopa Ki values against locomotor disability for patients with
progressive sapranadear palsy (FSP),No sign$cant correlation
was found: ANOVA-p = 0.52 putamen, p = 0.96 cadute;
Kendull-p = 0.14 putamen, p = 0.39 caudate. H c5 Y =
Hoehn and Yahr scalr 122).
decarboxylase (AADC) activity, which is present in
excess in dopaminergic neurons {2 I}. Consequently,
striatal '*F-dopa uptake does not provide a direct measurement of endogenous dopamine pools or production. AADC levels have been shown at postmortem to
fall to 88% and 37% of normal levels in the caudate
and putamen of patients with PD {301, paralleling our
observed levels of caudate and putamen '*F-dopa uptake in PD (84% and 48% of normal, respectively).
Three recent studies reported regional substantia nigra
pars compacta cell counts in PD at postmortem and
showed that these are reduced to 14 to 49% of normal
levels r31-331. It is likely, therefore, that our 18F-dopa
Ki values reflect the fraction of nigrostriatal dopaminergic neurons remaining, rather than providing a measure of their ability to generate dopamine from tyrosine.
Our patients with P D showed depression of striatal
l8F-dopa uptake compared to normal subjects, but
there was significant sparing of the function of the
head of caudate and the anterior putamen compared to
the severe involvement of the posterior putamen.
These findings are in agreement with previous PET
findings 1341, and also with postmortem striatal dopamine measurements. Kish and associates {351 demonstrated severe depletion of dopamine levels in caudal
posterior putamen, these being 10% or less of normal,
while by contrast caudate dopamine levels were as hgh
as 40% of normal. It is well recognized that the more
caudal and lateral cells of the substantia nigra pars compacts project to the putamen, while the rostral and
medial cells project to the caudate 1281. In PD the
ventrolateral nigral cells appear to be most susceptible
to Lewy body degeneration, and these cells project
primarily to the posterior putamen 128, 31, 33, 361.
The reason for the particular susceptibility of these
ventrolateral cells to Lewy body degeneration may be
related to the fact that they are relatively hypopigmented r33, 361. Melanin appears to bind free radicals,
and it is possible that reduced melanin levels in nig a l cells make them more susceptible to free-radical
damage.
Our patients with PSP showed a uniform, severe
depression of striatal '*F-dopa uptake, mean caudate,
anterior putamen, and posterior putamen Ki's being
reduced to 35 to 50% of normal. This finding of uniform striatal involvement in PSP is in agreement with
postmortem measurements of striatal dopamine levels
in PSP. Kish and colleagues {9] found that mean caudate and putamen dopamine levels were depressed to
20% and 25% of normal levels, respectively, in 5 patients with PSP, and Ruberg and coworkers [S} also
found similar involvement of the caudate and putamen
in their patients with PSP. Formal nigral cell counts
have not been reported in this syndrome, but Jellinger
and associates {6] noted global involvement of the
cornpacta in PSP, in contrast to the selective ventrolateral pathology of PD. In view of these pathological
findings, it is not surprising that our mean caudate and
putamen '*F-dopa Ki values in PSP were similarly depressed.
The striatal 18F-dopa uptake of our patients with
MSA was heterogeneous; some patients showed a
similar pattern to those patients with PD, with relative
sparing of caudate function, whereas others had the
PSP pattern of uniform striatal involvement. The mean
caudate '*F-dopa Ki value of the MSA group fell between the P D and PSP values. There was no clear
difference in the pattern of clinical involvement between the patients with MSA who had mild, and those
who had more severe, caudate involvement. None of
the latter had evidence of dementia, frontal lobe dysfunction, or the supranuclear gaze palsy characteristically present in PSP. Goto and coworkers 1311 carried
out cell counts of nigral dopaminergic neurons in 4
patients with striatonigral degeneration. Two of their 4
patients showed severe global nigral cell fallout, while
the other two showed relative presentation of medial
structures, confirming the heterogeneity of this condi-
Brooks et al: I8F-Dopa Uptake in Parkinsonian Syndromes 553
tion. Spokes and associates 121 also reported detailed
histopathological and neurochemical findings on 4 patients with MSA. The pattern of depression of striatal
dopamine levels resembled that seen in PD, with relative preservation of caudate levels, but cell loss from
the nigra appeared to be more extensive than that seen
in PD, the lateral two-thirds rather than just the ventrolateral area being extensively involved. Our variable
finding of mild to severe reduction of caudate 18F-dopa
uptake in patients with MSA is probably a measure of
the extent of their individual nigral involvement, and
may reflect a heterogeneity of underlying pathogenesis
of this syndrome.
Using both parametric and nonparametric statistics,
we found a significant inverse correlation between putamen 18F-dopa Ki values for individual patients with
PD and MSA, and their degree of locomotor disability
as measured by the Hoehn and Yahr scale [22] after
withdrawal of medication for 12 hours. The Hoehn
and Yahr scale is nonlinear, but reflects progressive
rigidity, bradykinesia, and instability of patients, using
a score from 1 (unilateral involvement) to 5 (severe).
Our findings suggest that the locomotor disability of
the patients with PD and MSA is primarily determined
by the degree of nigral disruption. This finding has
been previously reported in PD [37]. By contrast we
found no correlation between locomotor function and
striatal uptake of ‘*F-dopa in the patients with PSP.
This suggests that in contrast to PD and MSA, the
rigidity and instability of patients with PSP are less
influenced by the presence of nigral pathology.
The cause for this differential dependence of
locomotor function on the integrity of the dopaminergic pathways in PD, MSA, and PSP may be due to
their different patterns of regional cerebral pathology.
All three diseases involve severe degeneration of the
substantia nigra compacta {2, 5-61. In PD no significant degeneration of intrinsic striatal or pallidal
neurons occurs. In MSA striatal and external pallidal
degeneration is severe, while in PSP the striatum, internal pallidum, and brainstem nuclei are singled out.
Lesions of the striatal to internal pallidal projections
would be predicted to cause rigidity 138). It could well
be that locomotor function in PSP is determined by
striatopallidal, rather than nigral, integrity. If this were
the case, it would explain the lack of response of patients with PSP to L-dopa, as gamma-aminobutyric acid
(GABA), rather than dopamine, is the principal neurotransmitter of striatal and internal pallidal efferents.
The situation in MSA is more complex as the effects of
the striatal and external pallidal lesions characteristic of
this condition could in theory counterbalance one another {38]. If this were the case, it would explain the
greater dependence of locomotor function in MSA, as
opposed to PSP, on nigral integrity.
554 Annals of Neurology
Vol 2 8 No 4
October 1990
In summary, striatal ’*F-dopa uptake is globally reduced in PSP, but there is significant preservation of
anterior putamen and caudate function in PD. MSA
striatal function overlaps the PD and PSP groups. It
should be stated that none of our patients to date have
had pathological validation of their clinical diagnoses,
which were based on a set of clinical and radiological
criteria. In spite of this, our findings are in good agreement with those predicted from pathological studies.
As a general conclusion, it is reasonable to assume that
if 18F-dopauptake in the caudate and anterior putamen
is depressed to the same level as that in the posterior
putamen, the patient is likely to have neuropathological changes other than those of idiopathic PD. Our
findings may also be relevant to the current transplantation work that is being performed on patients with
PD, suggesting that fetal midbrain tissue would be best
sited in the more involved posterior putamen, rather
than the head of caudate or anterior putamen where
dopaminergic function remains relatively well preserved.
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