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Familial Progressive Supranuclear Palsy
Detection of Subclinical Cases Using 18F-Dopa and 18Fluorodeoxyglucose Positron Emission Tomography
Paola Piccini, MD;
Justo de Yebenez, MD;
Andrew J. Lees, MD;
Roberto Ceravolo, MD;
Nora Turjanski, MD;
Peter Pramstaller, MD;
David J. Brooks, MD
Arch Neurol. 2001;58:1846-1851.
ABSTRACT
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Background Progressive supranuclear palsy (PSP) is
generally considered to be a sporadic disease; however, occasional
cases of familial PSP have been described. The rarity of reports of
familial PSP may be attributed in part to an inability to detect
subclinical disease in affected relatives who subsequently die before
symptoms clinically develop.
Objective To study regional cerebral dopaminergic
function and glucose metabolism in members of 2 large kindreds with
familial PSP to identify subclinical cases.
Methods Three clinically affected members from the 2 PSP
kindreds were scanned with both 18F-dopa and
18fluorodeoxyglucose (18FDG) positron emission
tomography (PET). Fifteen asymptomatic first-degree relatives
were scanned with 18F-dopa PET; 10 of them also underwent a
second PET study with 18FDG.
Results All 3 clinically affected PSP patients showed a
significant reduction in caudate and putamen 18F-dopa
uptake along with a significant reduction in striatal, lateral, and
medial premotor area and dorsal prefrontal cortex glucose metabolism.
In 4 of the 15 asymptomatic relatives, caudate and putamen
18F-dopa uptake was 2.5 SDs lower than the normal mean.
These 4 subjects and a fifth asymptomatic relative with normal
18F-dopa uptake showed a significant reduction of cortical
and striatal glucose metabolism in a pattern similar to that of their
affected relatives.
Conclusion 18F-dopa and 18FDG PET
allowed us to identify 5 cases with subclinical metabolic dysfunction
among 15 subjects (33%) at risk for PSP, suggesting that this approach
is useful for characterizing the pattern of aggregation in PSP
kindreds.
INTRODUCTION
PROGRESSIVE supranuclear palsy (PSP) is a late-onset neurodegenerative
disease characterized by supranuclear vertical gaze palsy, postural
instability, rigidity, bulbar dysfunction, and dementia with the
variable presence of pyramidal and cerebellar signs.1, 2 It
is usually considered a sporadic disorder, even though a few familial,
pathologically proven PSP cases have been reported.3 In a
recent article concerning PSP kindreds from Europe and North America,
12 probands with 22 secondary cases with typical clinical PSP features
have been described.4 Thus, the apparent rarity of familial
PSP may reflect the difficulty in recognizing PSP cases in
epidemiological surveys. In particular, atypical presentations of PSP
cases may hinder accurate phenotypic assignment, and mortality owing to
other diseases may be responsible for a censoring effect with
subclinically affected relatives dying before symptoms develop.
Positron emission tomography (PET) has proven to be a
reliable method for detecting in vivo subclinical dysfunction in
degenerative diseases. 18F-dopa PET studies have shown that
25% of asymptomatic adult relatives of patients with familial
Parkinson disease (PD) and 55% of elderly asymptomatic co-twins of PD
patients show subclinical dopaminergic nigrostriatal
dysfunction5, 6; 11C-raclopride PET revealed
that 50% of asymptomatic adult carriers of the Huntington disease
IT15 gene had significant reductions in striatal dopamine
D2 receptor binding.7
In this study we used 18F-dopa and
18fluorodeoxyglucose (18FDG) PET to investigate
regional cerebral dopaminergic function and glucose metabolism in
clinically affected patients and their asymptomatic relatives from 2
kindreds with familial PSP. Our aim was to determine the prevalence of
subclinical cases with disease.
SUBJECTS AND METHODS
We studied 2 unrelated kindreds in which PSP was present across
several generations. The members of these families were referred to our
PET Centre from the Movement Disorder Clinics at the National Hospital
for Neurology, Queen Square, London, England (kindred 1) and from the
Fundacion Jimenez Diaz, Avenida de los Reyes Catolicos, Ciudad
Universitaria, Madrid, Spain (kindred 2). One of the 2
original probands (kindred 2) had died by the time of this study, and
postmortem analysis showed typical PSP neurofibrillary tangle disease.
In the antecedent relatives, the diagnosis of PSP was based on review
of hospital records.
The diagnosis of possible or probable PSP was made according to the
National Institute of Neurological Disorders and Stroke PSP society
criteria.8 Three affected subjects (2 from kindred 1; 1
from kindred 2) had an akinetic-rigid syndrome poorly responsive to
levodopa with onset at age 53, 60, and 70 years, respectively; 2 had a
supranuclear down-gaze palsy, whereas the third had slowing of vertical
saccades and prominent postural instability. All 3 PSP subjects had
axial rigidity, and 2 had a pseudobulbar palsy. Two of the 3 patients
had mild to moderate cognitive impairment of frontal type. (For more
clinical details see reference 4.) To establish the pattern of
dopaminergic and metabolic dysfunction in these families, we studied
the 3 clinically affected members with 18F-dopa and
18FDG PET
(Table 1).
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Characteristics of the Clinically Affected Members and of the Asymptomatic Members Studied With18F-Dopa and18FDG PET*
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All asymptomatic first-degree adult relatives aged 40 years or
older were asked to participate in the study. Fifteen subjects agreed
to undergo PET scanning with both 18F-dopa and
18FDG. All 15 relatives underwent 18F-dopa PET,
and 10 of them also underwent 18FDG PET. Of the other 5
that did not have 18FDG, 3 could not be rescanned for
technical reasons, and 2 subjects refused to have a second scan because
they experienced claustrophobia during the first scan.
The 15 asymptomatic relatives had no history of neurological illness
and had not taken drugs known to affect the dopaminergic system. At the
time of scanning, all underwent a full neurological
examination. Fourteen subjects had no signs or
symptoms of neurological disease, while 1 subject, aged 68 years
(kindred 2, III.3), had an isolated postural hand tremor. The
characteristics of these 15 subjects are detailed in Table 1B.
SCANNING PROTOCOLS
Permission for these studies was obtained from the Ethics
Committee of the Hammersmith Hospitals Trust, London. Approval to
administer radio-labeled ligands was obtained from the
Administration of Radioactive Substances Advisory
Committee of the United Kingdom. Written consent was obtained from all
subjects after a full explanation of the procedure.
The PET studies were performed using a camera at the Medical Research
Council, Cyclotron Building, Hammersmith Hospital, London (ECAT 953B;
CTI Inc, Knoxville, Tenn). This camera acquired data
simultaneously from 31 consecutive transaxial planes (slice separation,
3.4 mm with an average in-plane resolution of 6 mm full width at half
maximum). Scanning was performed with the orbitomeatal line
parallel to the detector rings. A 10-minute transmission scan, using a
retractable 68Ga/68Ge ring source, was
performed prior to the acquisition of the emission data to correct for
tissue attenuation.
18F-Dopa Scans
Prior to 18F-dopa injection, subjects were given oral
carbidopa, 100 mg, 1 hour before and 50 mg 5 minutes before the study
to block peripheral aromatic amino acid decarboxylase. A mean dose of
4.4 mCi (163 MBq) of 18F-dopa was infused into each subject
intravenously over 30 seconds, and the dynamic emission data were
acquired in 3-dimensional (D) mode as 25 time-frames over 95 minutes.
18FDG Scans
A mean dose of 4.7 mCi (174 MBq) of 18FDG was
administered to each subject by intravenous infusion over
30 seconds, and the data were acquired in 3-dimensional
mode as 24 time-frames over 60 minutes. In those subjects
who underwent both scans, the interval between PET studies was 2 to 7
days. 18F-dopa data were compared with those obtained from
a group of 19 age-matched control subjects (mean ± SD,
64 ± 12.1 years) and 18FDG data with those
of 8 control subjects (60 ± 14.5 years) scanned using
the same camera with the same protocols.
Data Analysis
18F-dopa.
The analysis was performed using in-house software written in Interactive Data Language
(Research System Inc, Boulder, Colo) on SUN Sparc workstations (SUN
Microsystems Inc, Palo Alto, Calif). Region-of-interest
(ROI) placement was defined with a standard template. We used
standardized regions: a 10-mm diameter circle ROI to sample head of
caudate and 10 x 24-mm elliptical ROI to sample dorsal
putamen aligned along the long axis. These regions were placed manually
by visual inspection on 3 contiguous planes encompassing the striatum.
Mean counts per pixel were measured for left and right caudate and
putamen in the last 14 time-frames corresponding to the period 25 to 95
minutes after injection. 18F-dopa influx rate constants
(Ki) were then calculated for the left and right caudate
and putamen using multiple-time graphical analysis with a nonspecific
occipital tissue input function.9 Two circular regions of
32-mm diameter were placed on the occipital lobes in the same planes as
those used to sample striatal regions and averaged to provide the
tissue input function. Comparisons of group means were made using
unpaired t tests. Individual putamen and caudate
Ki values were considered abnormal if they were more than
2.5 SDs lower than the normal group means.
18Fluorodeoxyglucose.
The analysis was performed
by applying statistical parametric mapping (SPM) to integrated images
of 18FDG activity spanning the last 20 minutes of the
dynamic scan to identify areas of significant altered regional cerebral
glucose metabolism in the PSP patients and the asymptomatic relatives
compared with the control group. The validation of
voxel-by-voxel statistical techniques to localize significantly
altered 18FDG uptake data has been recently
reported.10, 11 The SPM analysis showed the same findings
whether rCMRGlu (glucose regional cerebral metabolic rate) or
18FDG uptake datasets were used.10 We have
chosen to use SPM and 18FDG uptake data to avoid the
invasive arterial cannulation required to calculate rCMRGlu.
Integral 18FDG images for each subject were transformed
into standard stereotactic space.12 The template used in
this study was an 18FDG average image of 8
18FDG PET scans of healthy subjects normalized to the
standard SPM 95 flow template.10 The images were then
smoothed using a Gaussian kernel
(20 x 20 x 12-mm full width at half
maximum) to remove high-frequency noise from the images. The variance
in global cerebral metabolic rate for glucose across all subjects was
removed using analysis of covariance; between-group comparisons were
then performed with a t statistic on a voxel-by-voxel
basis.13 The first comparison aimed to identify differences
in regional 18FDG uptake between the 3 PSP patients and the
group of 8 normal controls to establish the pattern of metabolic
abnormalities in the clinically affected subjects; for this comparison,
significance was accepted if voxels survived an uncorrected threshold
of P<.001. In phantom experiments, this value of
significance has been shown to be sufficiently conservative to protect
against false-positive results.14
As most asymptomatic relatives would be expected to have
normal 18FDG uptake, a group analysis could mask those few
subjects with significant abnormalities. We therefore compared
individual scans for each asymptomatic subject against the group of 8
normal controls with the objective of finding a pattern of
18FDG uptake abnormalities in those with subclinical
disease similar to the affected relatives. For this comparison
significance was accepted if voxels survived at a corrected threshold
of P<.01. In this way we were able to identify 5 subjects
who had at least 1 area of abnormal 18FDG uptake in the
same region as those of the affected relatives. We then compared these
5 subjects as a group against the group of 8 normal controls.
RESULTS
CLINICALLY AFFECTED RELATIVES
18F-Dopa
Mean 18F-dopa caudate and putamen Ki
values (0.0051 ± 0.0011 min-1and
0.0049 ± 0.008 min-1) were significantly
reduced (P<.001) in the 3 PSP relatives compared with normal
subjects (0.0104 ± 0.0010 min-1and
0.0102 ± 0.009 min-1) (Figure
1).
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Figure 1. Caudate and putamen 18F-dopa Ki values
(min-1) in 19 controls (C), in 15 asymptomatic members of
the 2 families (A), and 3 clinically affected members (P).
Symbols filled in dark gray indicate the asymptomatic relatives in that
caudate and putamen 18F-dopa uptake is 2.5 SDs lower than
the mean caudate and putamen uptake values for the controls.
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18Fluorodeoxyglucose
The SPM analysis revealed areas of significantly reduced
18FDG uptake in bilateral lateral and medial premotor areas
(areas 6 and 8) (x, y, z = -24, -8, 56; z
score, 5.31; and x, y, z = 2, -2, 58; z score,
4.50), bilateral dorsal prefrontal cortex (area 10) (x, y,
z = -30, -58, 8; z score, 6.12; and x, y,
z = 50, -48, 12; z score, 5.80), right thalamus
(x, y, z = -4, 20, 8; z score, 4.86), and
bilateral striatum (x, y, z = -12, -6, 4; z
score, 6.46; and x, y, z = 8, -10, 4; z score,
6.32) (Figure 2) in the PSP
patients compared with controls. Increases in 18FDG uptake
were not found in any location.
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Figure 2. Areas of decreased 18fluorodeoxyglucose (18FDG)
uptake in 3 clinically affected members compared with 8 controls
(right) (P<.001) and in 5 asymptomatic members compared with
8 controls (left) (P<.001). Regions of decreased
18FDG uptake have been superimposed on a normalized
T1-weighted magnetic resonance imaging scan. PMC indicates premotor
cortex; DPFC, dorsal prefrontal cortex; BG, basal ganglia; and T,
thalamus.
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ASYMPTOMATIC MEMBERS
18F-Dopa
Four of the 15 asymptomatic relatives had 18F-dopa
caudate and putamen uptake values that were 2.5 SDs lower than the
normal mean (Figure 1). One subject was from kindred 1, and 3
subjects were from kindred 2 (Figure 3).
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Figure 3. Genealogical trees for kindreds 1 and 2. D indicates which subjects
have been scanned with 18F-dopa and G with 18fluorodeoxyglucose.
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18Fluorodeoxyglucose
The comparison of individual scans for each asymptomatic relative vs
the control group identified 5 subjects with areas of significantly
decreased regional glucose uptake.
Four of them were also subjects with reduced
striatal 18F-dopa Ki values. In these 4
subjects, we found cortical and subcortical reductions of
18FDG uptake similar to those found in their affected
relatives. A fifth asymptomatic relative, with normal striatal
18F-dopa uptake, showed a reduction of 18FDG
uptake in the lateral premotor cortex and dorsal prefrontal cortex (x,
y, z = 40, -22, 50, maximal z score, 3.17; and
x, y, z = -46, -54, 8, maximal z score, 3.84,
respectively).
The voxel-by-voxel analysis applied to these 5 asymptomatic
members as a group showed significant decreases in 18FDG
uptake in bilateral lateral and medial premotor areas (x, y,
z = -30, -14, 56; z score, 5.31; and x, y,
z = 10, -6, 52; z score, 4.24), right dorsal
prefrontal cortex (x ,y, z = -46, -54, 8; z
score, 5.42) and bilateral striatum (x, y, z = -6, -16,
8; z score, 4.7; and x, y, z = 20, -12, 8;
z score, 4.15) compared with controls (Figure 2).
Figure 3 shows the genealogical trees for kindred 1 and kindred 2. The
members scanned with 18FDG and/or 18F-dopa and
those asymptomatic subjects with abnormal scans are also indicated.
COMMENT
In our familial PSP patients, striatal 18F-dopa uptake was
significantly reduced bilaterally, with putamen and caudate being
similarly affected. Such a uniform reduction of dopamine storage
throughout the striatum has also been reported for sporadic idiopathic
PSP patients15, 16, 17, 18 and suggests that the substantia nigra in
PSP patients is globally involved. Glucose metabolism was also reduced
in the striatum of our patients, in agreement with findings reported
for sporadic PSP patients19, 20, 21 and in contrast to findings
for patients with PD in which striatal 18FDG uptake is
preserved.19 The reduction in premotor, prefrontal, and
thalamic glucose metabolism that we have found in our familial PSP
members is also typical of patients with sporadic PSP,19, 20, 21, 22
although other areas, such as
parietal cortex and cerebellum, have also been
reported to be involved in this condition.23
Four of 15 asymptomatic relatives (27%) showed reductions in striatal
18F-dopa and 18FDG uptake bilaterally. These 4
subjects also had decreased 18FDG uptake in a pattern
similar to that of their clinically affected relatives; cortical
glucose metabolism was reduced in lateral and medial premotor areas and
right dorsal prefrontal cortex, while left dorsal prefrontal cortex and
thalamus were spared. In addition to these 4 relatives, we identified a
fifth asymptomatic subject with normal striatal 18FDG and
18F-dopa uptake who had reduced glucose metabolism in the
premotor cortex bilaterally and the right dorsal prefrontal cortex. If
we include this last subject, the percentage of asymptomatic adult
relatives with abnormal PET findings increases to 33%.
Since the pattern of cerebral glucose hypometabolism and reduction of
18F-dopa uptake in the clinically asymptomatic relatives is
similar to that observed in the cases with established disease, we
assume that these 5 among the 15 subjects at risk for PSP indeed have
subclinical disease. In support of this assumption, 1 of the relatives
with abnormal 18F-dopa and 18FDG scans
developed clinical PSP 2 years after scanning at age 59 years (kindred
2, III.26). When we arbitrarily divided the asymptomatic
relatives who underwent PET scanning into groups older and younger than
age 50 years, we observed that none of the 4 subjects younger than 50
years had subclinical abnormalities, while the percentage of
subclinical abnormalities among the 11 subjects who were aged 50 years
or older rose to 45%. Since the mean age of onset of the disease in
the two families is 61 years, this additional finding implies that the
duration of the subclinical phase of PSP, at least in these families,
is only a few years.
The reduced 18FDG uptake in the frontal cortex
of some asymptomatic relatives suggests that frontal cortex
hypometabolism constitutes an early disease marker. In agreement with
this hypothesis, a previous 18FDG PET/neuropsychological
study conducted in a cohort of 41 PSP patients in different
stages of the disease reported that, although frontal glucose uptake
decreases with disease duration, frontal hypometabolism is already
present in the very early stage of the disease and precedes the onset
of overt frontal lobe deficits.22
In 1 of our asymptomatic subjects, 18FDG uptake was found
only to be reduced in cortical areas with sparing of subcortical
structures. In early reports of PSP, the cortex was thought to be
spared,24 and this led to the concept of a "subcortical
dementia" supposedly owing to an impairment of afferent stimulating
systems, maybe reticular or thalamic in origin.24, 25
Subsequent postmortem studies have consistently reported
neurofibrillary tangles in frontal cortex,26, 27, 28, 29 suggesting
that at least some of the intellectual deficits in PSP are owing to
lesions in the cortex itself.29 The finding in 1 of our
asymptomatic subjects of cortical hypometabolism in a pattern similar
to that of his affected relatives but without subcortical involvement
supports the idea that some of the dysfunction in PSP is cortical in
origin and can occur very early.
The presence of subclinical cases detected with 18F-dopa
and 18FDG PET in asymptomatic members of PSP families
suggests that the familial aggregation for this disease is greater than
that ascertained on the basis of
clinical surveys alone, indicating that PSP could
have a greater hereditary component than previously realized. Factors
that may explain the difficulty in recognition of familial cases of PSP
on the basis of clinical findings include the late onset of the
condition and the presence of occasional atypical cases given the
variation in clinical phenotype. The typical syndrome is characterized
by a variable combination of supranuclear ophthalmoplegia, axial
dystonia, akinesia, pseudobulbar palsy, and mild
dementia.30, 31 However, PSP can present with atypical
clinical pictures, including a pure akinetic syndrome and pure
dementia.30, 32, 33 Recently, an elderly patient with
pathologically confirmed PSP has been described who had a pure
psychiatric syndrome without neurological signs.34
The prevalence of PSP in the United States35 is reported to
be 77 times lower than the prevalence of PD,36 while, in
contrast, the incidence of PSP37 has been reported to be
only 12 times lower than that of PD.36 Although the median
survival time from symptom onset is shorter in PSP37 than
in treated PD patients,38 survival differences cannot
explain the discordance in incidence and prevalence rates reported for
PSP.31 With current clinical diagnostic tools, PSP patients
are diagnosed late in their disease course, and many PSP patients die
with other diagnoses,39, 40 so it is likely that clinical
prevalence estimates have been grossly underestimated.31
There have been a few previous reports of familial cases with
pathologically confirmed PSP. To date, familial clustering of PSP has
been reported in a total of 20 kindreds.4 The pattern of
inheritance in these reports was variable but generally suggestive of
dominant transmission. Higgins et al41 suggest that PSP can
also be inherited as an autosomal recessive disorder linked to the
TAU gene, but these data have not been confirmed. Other
familial PSP clusters need to be recognized and included in a wider
genetic search.
In conclusion, we have used 18F-dopa and 18FDG
PET to assess clinically affected and asymptomatic adult members of 2
kindreds with familial PSP. Cortical and subcortical glucose and
dopaminergic metabolic abnormalities with a pattern similar to that of
their clinically affected relatives were found in 33% of asymptomatic
adult members, suggesting that these subjects have subclinical PSP. The
possibility of detecting subclinical cases and atypical phenotypes by
using 18F-dopa and 18FDG PET could therefore
improve the diagnostic recognition of PSP cases and be a valuable aid
in finding a gene or genes responsible for this disease.
AUTHOR INFORMATION
Accepted for publication April 3, 2001.
From the Medical Research Council Clinical
Sciences Centre, Imperial College School of Medicine, Hammersmith
Hospital, London, England (Drs Piccini, Ceravolo, Turjanski,
and Brooks); Department of Neurology, Fundacion Jimenez Diaz,
Universidad Autonoma de Madrid, Madrid, Spain (Dr de
Yebenez); Institute of Neurology, Queen Square, London (Drs
Lees and Brooks); and the Department of Neurology, Regional General
Hospital, Bolzano, Italy (Dr Pramstaller).
Corresponding author and reprints: Paola Piccini, MRC Clinical Science
Center, Cyclotron Unit, Hammersmith Hospital, DuCane Road, W12 ONN
London, England (e-mail: paola.piccini{at}csc.mrc.ac.uk).
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