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Dopaminergic function in familial Parkinson's disease A clinical and 18F-dopa positron emission tomography study.

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Dopaminergic Function in Familial Parkinson’s
Disease: Clinical and 18F-DopaPositron
Emission Tomography Study
P. Piccini, MD,* P. K. Morrish, MRCP,* N. Turjanski, MD,* G. V. Sawle, DM,* D. J. Burn, MD,*
R. A. Weeks, MD,* M. H. Mark. MU,? D. M. Maraganore, MD,+A. I. Lees, MD,5 and D. J. Brooks, MD*S
There is increasing evidence for familial aggregation in Parkinson’s disease (PD). It is possible that some asymptomatic
relatives of I’D patients have subclinical nigral Lewy body pathology and their identification could help determine the
true prevalence of the disease. We used 18F-dopapositron emission tomography to investigate nigrostriatal dopaminergic
terminal function in asymptomatic members of 7 unrelated kindreds in which at least 2 members had parkinsonism.
Eight (25%) of the 32 asymptomatic relatives showed abnormal putamen I8F-dopauptake (2.5 standard deviations below
the normal mean). When discriminant function analysis was applied, all of these 8 subjects plus another 3 were classified
with high probability as having PD. On neurological examination, 5 of the 32 relatives scanned had an isolated mild
postural tremor and 2 of these 5 had reduced putamen uptake. Our findings provide further support for a role of
inheritance in the etiology of PD and suggest that the penetrance for nigrostriatal dopaminergic dysfunction in familial
clusters of PD is higher than the prevalence of clinical parkinsonism reported in epidemiological surveys.
Piccini P, Morrish PK, Turjanski N, Sawle GV, Burn DJ, Weeks RA, Mark MH, Maraganore DM,
1,ees AJ, Brooks DJ. Dopaminergic function in familial Parkinson’s disease: a clinical and ”F-dopa
positron emission tomography study. Ann Neurol 1997;41:222-229
Parkinson’s disease (PD) is a common neurodegenerative disease whose incidence rises with age and which
is characterized pathologically by the presence of nigral
Lewy bodies. It has been hypothesized that the disease
may be due to an as yet unknown environmental factor
causing a nigostriatal insult, which along with cell attrition due to normal aging results in clinical PD when
cell loss falls below a critical threshold. T h e existence
of many families in which a number of individuals of
different generations present with typical P D [ 1-5)
suggests, however, that there may also be a genetic contribution to the etiology of PD. Whether these families
represent one end of a spectrum of genetically determined disease with variable penetrance or whether they
actually represent a disorder different from sporadic idiopathic PD is still uncertain [6].
In many PD patients a pattern of familial aggregation is not obvious, but it has been proposed that familial disease may be masked in patients with apparently sporadic disease by either genetic anticipation [791 or the censoring effect of mortality due to other
diseases; that is, subclinically affected antecedent rela-
tives die before symptoms clinically develop [ 101. This
censoring effect may be very large in a disease that is
late onset, as has already been shown for Alzheimer’s
disease [ 1 13.
T h e prevalence of nigral Lewy bodies at autopsy in
populations over the age o f 7 0 is about 10% [12, 131
whereas the prevalence of clinical I’D in the population
over the age of 70 lies between I Yo and 2% [ 141.“Incidental” Lewy body disease may therefore represent a
presymptoniatic phase of PD [l5]. Based on these observations it is clear that epidemiological surveys of
clinical PD are likely to miss a significant population
of subjects who have only subclinical involvement and
so underestimate the true prevalence of nigral Lewy
body disease. “F-dopa positron emission tomography
(PET) is a sensitive marker of dysfunction of the nigrostriatal dopaminergic system [ 16-20], In previous reports it has provided an in vivo means of detecting
subclinical striatal abnormalities in co-twins of PD patients [21, 221 and in an Irish kindred with parkinsonism [23].
I n this study we used ”F-dopa PET to estimate the
From the *Medical I<esc.irch Council Cyclotron Unit, Hammersmith Hospital, L.ondon; tNrw Jersey-Roberr Wood Johnson Mcdical School, N e w Rrunswick, NJ; $l>epirrnieiit of Neurology, Mayo
C l i n i c . Kochesrer, MN; ~ n dW‘irional Hospital for Neurology,
I.ondon, IJnired Kingdom.
Received Ilec 19, 1305, a n d in revised form May 28 md JuI 26.
1096. Accepted for pd)licnrion Aug 5, 1996.
Address cori-rspondence r o Dr l’iccini,
Copyright 0 1997 by the American Neurological Association
M K C Cyclorron Unit. Hamw,
The genealogical tree for each kindred is shown in Figure
1 and clinical details of the patients with parkinsonism are
prevalence of subclinical nigrostriatal dysfunction in a
series of unrelated PD kindreds in which a t least 2
affected members had levodopa-responsive parkinsonism.
shown in Table 1 .
A t least 1 affected individual from cach family was studied
with IXF-dopaPET. All the affected patients from Kindreds
1, 2,3, 4, 5, and 7 presented with levodopa-responsivc parkinsonism clinically indistinguishable from idiopathic PLI.
One affecred patient in Kindred 6 had atypical disease with
rapid progression and associated dementia. H e died of aspiration pneumonia at the age of 33 and postmortem examination revealed marked neuronal loss in the ventrolateral substantia nigra together with numerous L e y bodies. Corcical
L e y bodies were also present and detectable without requiring immunostaining. His brother had a levodopa-responsive
akinctic-rigid syndrome with no atypical features or demen ria.
Thirty-two asymptomatic relatives from rhese 7 differcnt
families agreed to undergo PET. They had no significant
Subjects and Methods
Family Members
Seven unrelated kindreds were studied. The probands of
these families were referred to our unit from the Movement
Disorder Clinics ar the National Hospital for Neurology,
London, United Kingdom (UK) (Kindreds 1, 3, and 4); the
Hammersmith Hospital, London, U K (Kindreds 2,5 , and
7); and the Robert Wood Johnson Medical School, New
Brunswick, NJ (Kindred 6). When a positive history for familial parkinsonism was identified in a family, the diagnosis
was verified through medical records or by clinical examination by one of the authors, or by both means.
Fig 1. Genealogical trees to the 7 kindreds. 7 = proband; 0 = male; 0 = female; 0 = dectased; 0, = isolatedposrural tremor; a, W = Parkinson: disease; * = PET scanning;
= abnormal "F-dopa putamen uptake (2.5 SD below
the normal mean); ~..i = outlined portions of the pedigrees include those individuals residing in dzfferent countries jiorn the country of origin ofthe family.
kindred 5
Piccini et al: Dopaminergic Function in Familial P D
Ezhle 1. Clinical Details of the Patients with Paarkinsonism and of the Asymptomatic Relatives Who Had “F-Dopa PET
Asyinp toma tic Relatwcs
I’,irkinsoni.iii Oatientb
Mcan Agc
at Onact
N ~of.
to Affcrtcd
Respon5e to
(pr I
SLj) Trcatmznr
No. of
i 4
2 10 Yes
2 7
2 9
Dementid 7
history of neurological illness and had not taken drugs
known to affect the dopaminergic system. A full neurological
examination was performed by one of us (P. P.) in all the
subjects studied: In 27 subjects there were no abnormal neurological signs, while 5 had an isolated mild postural tremor.
Table 1 summarizes their clinical characteristics.
In total, 42 family members were studied with ‘8F-dopa
PET: 10 parkinsonian subjects and 32 “unaffected” relatives.
Ethical permission for these studies was obtained from the
Ethics Committee of the Royal Postgraduate Medical School,
Hammersmith Hospital. Approval to administer radiolabeled
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.
Scans were performed on the CTI 9.31 /12/8 (CTI, Knoxville, TN) scanner in the Medical Research Council (MRC)
Cyclotron Unit at Hammersmith Hospital. The performance
characteristics of this camera have been described [ 2 4 ] .The
final reconstructed spatial resolution for 15 simultaneously
acquired slices is 7.0 X 8.5 X 8.5 nini (at full-width halfmaximum). Scanning was performed with the orbitomeatal
line parallel to the detector rings. A 10-minute transmission
scan, using a retractable ““Ga/%e r‘tng source, was performed to correct for tissue attenuation. Subjects were given
carbidopa, I00 mg 1 hour before and 50 mg 5 minutes
before the study, to block peripheral aromatic amino acid
decarboxylase. A mean (F standard deviation [SD]) dose of
136 (t46) MBq of “F-dopa was administered to each subject by intravenous infusion over 2 minutes. Dynamic emission data were collected in 25 time frames over 90 minutes.
The data were analyzed using image analysis software (Mayo
Foundation, Rochester, MN) on SUN SPARC workstations
(Sun Macrosystem, Mountain View, CA). The position of
striatal structures was determined by inspection with reference to the stereotactic atlas of Talairach and Tournoux (251.
Region-of-interest (ROT) placement was defined using a standard template as previously described [ 171. “F-dopa influx
constants (4)were calculated for the right and left caudate
and putamen using a multiple time graphic analysis (MTGA)
Annals of Neurology
Vol 41
No 2
Februaiy 1997
01 1
(No Signs1
Trcin or)
Mean Age
(yr i SD)
(1st Degree1
36.2 ? 12
58.8 t_ 1 1
45.5 t I 1
36.7 i 10
58.0 t 3
35.3 t 16
51 1
I 13
61 1
approach [26]. The MTGA was modified by using a nonspecific occipital tissue rather than plasma input function [27,
Results were compared with findings for a group of 33
control subjects (mean age, 59.5 f 15 years) and from a
group of 18 presumed sporadic PD patients (mean age, 54.2
i- 18 years) scanned using the same camera and the same
scanning protocol. The sporadic parkinsonian patients had
a niean disease duration of 7.1 f 4.8 years and a mean
Hoehn and Yahr staging of 2.7 -t 0.9 and were taking a
mean of 750 mg of [.-dopa (with carbidopa or benserazide)
Statistical Analysis
Right and left putamen
and caudate K, values were averaged for each subject. Comparisons of group means were made using Student’s unpaired
t test. Individual averaged left-right putamen and caudate k;
values were considered abnormal if they were more than 2.5
SDs below the normal group means. Fisher’s exact test was
also used within the group of asymptomatic subjects to compare the frequency of reduced IXF-dopa uptake in subjects
with and those without isolated postural tremor.
L>ISC:RIMINANT FUNCI‘ION ANALYSIS. The values for individual left and right putamen and caudate uptake in control
and sporadic PD cohorts were used to define the discriniinant function used for the analysis (SPSS version 4.0, SPSS
UK Ltd, Surrey, England). “F-dopa PET findings for patients with familial PD and asymptomatic members of the
kindreds were then subjected to discriminant analysis and
on the basis of these, each individual was assigned to a probability of having PD.
Table 2 shows the mean left-to-right caudate and putamen “F-dopa K , values for the groups of 33 normal
control subjects, 18 sporadic PD patients, 10 affected
members of the parkinsonian kindreds, and their 32
asymptomatic relatives. The cohorts with sporadic PD
and familial parkinsonism had significantly
(p <
Table 2.Averaged Lefi-to-Right Putamen and Caudate I8F-dopa Injux Constants (K,) for Normal Subjects, Sporadic PD
Patients, Familial PD Patients, and "Unafected" Relative?
Age (yr)
Normal control subjects
Sporadic PD
Familial PD
Unaffected members (all)
No signs
Isolated postural tremor
0.0110 (0.0017)
0.0079 (0.0025)h
0.0070 (0.0024)h
0.0101 (0.0016)
0.0100 (0.0019)
0.0103 (0.0010)
(0.00 10)
'Data are given as mean (SD).
"p < 0.001 compared with normal control values
0.001) reduced mean putamen and caudate k; values
in comparison to the normal values. In both sporadic
and familial PD groups the reduction in putamen values approached twice that of the caudate; no statistical
difference was found in '*F-dopa uptake between these
two groups of parkinsonian patients. The mean putamen K , value of the entire asymptomatic group of 32
relatives was also significantly ( p < 0.001) reduced
compared with that of normal control subjects. When
mean putamen k; values for relatives with no signs (27
patients) and with isolated postural tremor on examination ( 5 patients) were compared separately, K , values
for both subgroups were also significantly reduced by
17% and 23%, respectively ( p < 0.001) in comparison
to the normal group. Mean caudate "F-dopa uptake
was normal for the group of asymptomatic relatives.
Fig 2. Representative transaxial images of striatal "F-dopa activiy, collected 30 to 90 minutes ajer tracer inhsion, f i r a patient
with familial parkinsonism (Patient III.12>Kindred 2), an asymptomatic family member (Subject 111.4,Kindred 2), and a control subject. The image for the patient with parkinsonism shows a severe reduction in "F-dopa uptake, particularly affecting the
putamen. The middle image for the asymptornatic relative shows putamen I8F-dopa uptake that is intermediate between that of
the nonnal subiect and the affected relative.
Piccini et al: Dopaminergic Function in Familial PD 225
Figure 2 shows representative transaxial images of
striatal "F-dopa activity, collected 30 to 90 minutes
after tracer infusion, for a patient with familial PD, an
asymptomatic family member, and a control subject.
Based on a reduction greater than 2.5 SDs below
the normal mean as the threshold for significant impairment of tracer uptake, 8 (25%) of the 32 asymptomatic members had significantly reduced left-to-right
averaged putamen '*F-dopa uptake (Subject 11.9 of
Kindred 1; 11.3 and 111.5 of Kindred 2; 11.6 of Kindred
3; IV.3 of Kindred 4; 111.7 of Kindred 5; 1.1 and 11.1
of Kindred 6). Two of these subjects (11.3 of l n d r e d
2 and 11.6 of Kindred 3) had isolated postural tremor
on clinical examination. Figure 3 shows a scatter diagram of individual averaged left-to-right putamen li;
values for the 32 asymptomatic relatives.
The mean "F-dopa putamen and caudate uptake
values were not significantly different for the asymptomatic subjects with and those without isolated postural tremor. The frequency of reduction of putamen
i R F-dopa uptake was not significantly different in those
subjects with postural tremor compared to those without tremor (Fisher's exact test, p = 0.604).
Based on discriminant analysis, all the familial PD
patients were correctly assigned to the PD category
with a probability higher than 0.99. The probability
of the 33 normal subjects belonging to the control diagnostic category was 0.99 or higher for 31 subjects,
and 0.89 and 0.93 for 2 others. Nine of the 32 asymptomatic relatives (11.4 and 11.9 of Kindred 1; 11.3 and
111.5 of Kindred 2; 11.6 of Kindred 3; IV.3 of Kindred
4; 111.7 of Kindred 5; 1.1 and 11.1 of Kindred 6) were
classified as having PD with a probability of 0.99 or
higher. Two other relatives were classified as having
PD with a probability of 0.68 (IV.2 of Kindred 7) and
0.72 (111.2 of Kindred 1). The other 21 asymptomatic
Ki (min '1
0 014
Fig 4. Discriminant analysis based on individual hemispheric
putamen and caudate K, values. Probability of belonging to
the Y'D '' category f i r each of 32 asymptomatic relatives stud0 = isolated
ied with PET. 0 = male; 0 = female; 0,
postural tremor; *3 = subsequently developed parkinsonism.
relatives were all classified as normal with a probability
of 0.98 or higher (Fig 4). O n clinical follow-up, 3 relatives (111.9 and IV.2 of Kindred 1 and 11.3 of Kindred
2) subsequently developed a syndrome clinically indistinguishable from PD (7 months, 4 years, and 2 years,
respectively, after their PET study). Two of them (IV.2
of Kindred 1 and 11.3 of Kindred 2) had putamen "Fdopa k; values that fell below the 2.5-SD cutoff and
on the basis of discriminant analysis were classified at
the time of the scan as PD patients with a probability
of 0.99. The other subject (111.9 of Kindred 1) had
putamen uptake in the low range of normality and was
classified by discriminant analysis at the time of PET
as having PD with a probability of 0.72 (see Figs 3,
0 01 1
Normal control
0 009
0 008
0 007
0 006
n o onooo.
1.5 SDs
Fig 3. Scatter plot o f "F-dopa averaged lefi-to-right putamen
K,values f i r the 32 asymptomatic relatives studied with
PET 0 = male; 0 = female; 0, = isolatedpostural
tremor; 0 = subsequently developed parkinsonism.
Annals of Neurology
Vol 41
No 2
February 1997
This "F-dopa PET study demonstrated abnormally reduced putamen uptake in 8 (25%) of 32 asymptomatic
members of families in which multiple individuals were
affected with parkinsonism. These 8 subjects, plus another 3, were assigned to a PD diagnostic category with
high probability by discriminant analysis.
Striatal uptake of "F-dopa reflects nigrostriatal nerve
terminal aromatic amino acid decarboxylase activity
[29] ; however, the significance of finding reduced '*Fdopa putamen uptake in a clinically normal subject still
has to be determined. There is evidence to suggest that
reduced striatal I8F-dopa uptake in asymptomatic subjects may indicate subclinical parkinsonism. In 1985,
Calne and coauthors [30] reported that 2 of 4 human
subjects who had been exposed to 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine(MPTP) but had no clinical
evidence of parkinsonism had reduced striatal IXF-dopa
uptake; in addition, a subject scanned as a normal control who had reduced striatal "F-dopa uptake subsequently developed signs of parkinsonism [31]. However, it is difficult to be sure whether abnormal "Fdopa uptake in clinically normal subjects represents a
fixed subclinical dopaminergic defect or whether it represents a pathological condition bound to progress to
clinical disease. Several workers, on the basis of premorbid personality assessment, wrote in the past decade that the prodromal phase of PD may extend over
decades [32, 331. Recent estimates of the preclinical
period in PD patients on the basis of extrapolation of
pathological and PET data vary from 3 to 5 years [34,
351 to 40 to 50 years [36, 371. As the clinical rate of
the progression of the disease is highly variable in different individuals [38], the length of the preclinical
phase is also likely to be variable.
In our study 3 relatives who were asymptomatic at
the time of "F-dopa PET but were classified on the
basis of the discriminant function analysis as having
PD (with probabilities of 100, 0.99, and 0.72) subsequently developed clinical parkinsonism. The first of
them (111.4 of Kindred 1) was originally reported by
Sawle and colleagues [23]; he became parkinsonian
within a year of his scan. The other 2, a young lady
from the same family (IV.2) and a 72-year-old lady
from Kindred 3, developed parkinsonian signs within
4 and 2 years of their scans, respectively.
Our findings are therefore highly suggestive that reduced "F-dopa uptake reflects nigrostriatal dysfunction
in asymptomatic relatives and that these individuals
may be subclinically affected by the same disease process as clinically affected individuals.
Langston and Koller [39] suggested that PD exists
in several phases: a disease-free state in which risk factors are present, a presymptomatic phase in which the
disease begins and progresses, and a symptomatic phase
after the disease has reached the symptomatic threshold. The members of our families may share common
genetic risk factors predisposing toward nigrostriatal
dopaminergic dysfunction. Differences in gene penetrance or in exposure to endogenous or exogenous toxins may account for the differences between these subjects in their progression toward the clinical state of
The existence of a subclinical phase has been established in other neurodegenerative disorders such as
Huntington's disease (HD). Studies with "C- SCH
23390 and "C-raclopride PET are able to derect preclinical dysfunction in asymptomatic adult HD gene
carriers [40].
The presence of relatives with subclinical nigrostriatal dysfunction in our 7 unrelated kindreds indicates
that epidemiological surveys of PD for which patients
are classified on purely clinical grounds may underestimate the true prevalence of familial aggregation in PD.
Gowers in 1903 noted that approximately 15% of
PD patients reported having an affected relative. It has
been argued that since PD is common, with a lifetime
incidence rate of 2.5%, chance alone could account
for this finding [41]. Conclusions drawn from other
epidemiological familial aggregation studies have varied, possibly reflecting their different methodologies.
Recent case-control studies, conducted with rigorous
epidemiological methods, demonstrated significant familial aggregation in PD and an increased risk for the
development of PD in relatives of patients. Semchuck
and coauthors [42] reported that 23 of 128 patients
had a positive family history for PD compared with
15 of 255 control subjects; Bonifati and colleagues [43]
found that 24 (24%)of 100 consecutive idiopathic PD
patients had a family history of PD compared with 6%
of matched control subjects. These data suggest that
familial aggregation is not accounted for by chance
alone, but does not distinguish between either a genetic
or an environmental etiology for parkinsonism.
In our study we identified no differences in exposure
to environmental factors between affected (clinically
and with abnormal PET) and unaffected members of
our kindreds. Moreover, in all our families the calendar
year of onset varied considerably within families, the
difference in calendar year of onset ranging from 16
to 60 years, while the age at onset across generations
was similar. These findings argue against a shared environmental insult and for a genetic etiology of the parkinsonism in the families we studied.
The first evidence that PD might be a genetic disorder was obtained by Mjones in 1949 [44]. He examined 194 PD patienrs and their families in Sweden and
concluded that PD is transmitted as an autosomal
dominant disease with incomplete (60%) penetrance.
This study was subsequently criticized for categorizing
patients with isolated postural tremors or with dementia as affected [GI. Recently, a role for inheritance in
PD was proposed again following clinical surveys by
Maraganore [45] Lazzarini [46],and Payami and their
respective colleagues [47].These studies suggested that
if PD has a genetic basis, it would best fit an autosomal
dominant mode of inheritance with reduced penetrance.
A clear-cut pattern of autosomal dominant inheritance is present in 4 of our 7 families (Kindreds 3, 4,
5, and 7 ) .In Kindreds 1, 2 and 6 the pattern is suggestive of autosomal dominant but mitochondria1 inlieritance cannot be excluded.
In the last two decades an increasing number of pedigrees with multiple members with parkinsonism have
been reported [1-5, 48, 491 and most of these pedigrees exhibit an autosomal dominant mode of inheri-
Piccini et al: Dopaminergic Function in Familial PD
tance. Whether these families have “idiopathic” PD or
represent a clinically similar familial disorder is unclear.
Maraganore and colleagues [45] concluded that there
is a familial form of PD that is indistinguishable from
the sporadic form. Lazzarini and associates [46] found
a positive family history in 46 (22Yo) of 21 1 consecutive patients and the proportion of probands with
definite family history rose to 40% when pedigree information was complete through to second-degree relatives; the authors suggested that this implies that many
ostensibly “sporadic” cases of PD would emerge as familial if a fully informative history were available.
A number of families with dominantly transmitted
parkinsonism associated with Lewy body pathology at
postmortem have been documented [2, 3, 491 in which
the intrafamilial variation in clinical features is similar
to the individual range of manifestations generally seen
in sporadic PD. In a recent report, Duvoisin and Golbe
[50] concluded that data from these different kindreds
with PD suggest that mutation of a single gene may
account for PD in each of these families, as well as in
nonfamilial PD.
Three of our 5 multigeneration PD families (Kindreds 1, 2, and 7 ) showed the presence of clinical anticipation, the reduction in mean age at onset of PD between generations being 20 years in Kindred 2, 18
years in Kindred 1, and 10 years in Kindred 7. Anticipation was not evident in Kindreds 4 and 5. Until
recently, anticipation has not been associated with PD,
but now a number of studies reported earlier onset of
PD in successive generations [ 5 , 7-91. This association
of PD with anticipation suggests that an expanded trinucleotide repeat sequence may be involved in the
pathogenesis of the disease; however, this hypothesis
has not been confirmed [5I].
The finding of isolated postural tremor in relatives
of PD patients has long been considered a confounding
problem in studies of the prevalence of familial PD
and its genetic analysis. Five of our 32 asymptomatic
relatives had isolated mild postural tremor at the time
of their PET scans and 2 of them had abnormal ‘‘Fdopa putamen uptake. However, the frequency of reduced ‘*F-dopa uptake was no greater in those subjects
with isolated postural tremor than in those without,
suggesting that nigrostriatal dopaminergic dysfunction
alone does not account for the presence of postural
tremor in relatives of patients with familial PD.
In conclusion, we used PET and ‘*F-dopato examine
apparently unaffected members of kindreds with familial
parkinsonism. W e found a high proportion of relatives
(25%) with abnormally reduced putamen ‘*F-dopa uptike, suggesting that some “unaffected” members have
subclinical nigrostriatal dysfunction. The data indicate
that the penetrance of nigrostriatal dysfunction in familial
clusters of parkinsonism is higher than that reported in
Annals of Neurology
Vol 41
No 2
February 1997
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Piccini et al: I3 ipaminergic Function in Familial PD
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