Brain, Vol. 125, No. 10, 2248-2256,
October 2002
© 2002 Oxford University Press
Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study
1 MRC Clinical Sciences Centre, and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, 2 Neurogenetics Unit, Institute of Neurology and 3 Reta Lila Weston Institute of Neurological Studies, Royal Free Hospital and University College Medical School, London, UK
Correspondence to: P. Piccini, MRC Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK E-mail: paola.piccini{at}csc.mrc.ac.uk
Received November 21, 2001. Revised March 27, 2002. Accepted April 24, 2002.
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Molecular and clinical characterization of parkin-associated parkinsonism is well described; however, there are no data available on progression of dopamine terminal dysfunction in parkin-associated disease. We have used [18F]dopa PET serially to study members of a family with young-onset parkinsonism who are compound heterozygous for mutations in the parkin gene, having an exonic deletion and a novel intronic splice site mutation. Four patients have been studied twice, 10 years apart, to assess disease progression. Additionally, we have studied five asymptomatic family members, four of whom carry a single parkin mutation and one individual who has a normal genotype. Two of the carriers and the individual with the normal genotype had repeat [18F]dopa PET. The group of parkin patients showed a significantly slower loss of putamen [18F]dopa uptake (P = 0.0008) compared with a group of idiopathic Parkinson’s disease (IPD) patients who had baseline putamen [18F]dopa uptake and disease severity similar to the parkin group. These results indicate that disease progression in patients with parkin mutations is slower than that of IPD patients. The group of asymptomatic parkin carriers also showed significant striatal dopaminergic dysfunction, and three of them developed subtle extrapyramidal signs. However, the two carriers scanned twice showed no progression over a 7-year period. The slower rate of disease progression in parkin patients may explain the near normal longevity of these patients with young onset parkinsonism.
Keywords: PET; progression; parkin mutations
Abbreviations: H&Y= Hoehn and Yahr score; IPD = idiopathic Parkinson’s disease; UPDRS = Unified Parkinson’s Disease Rating Scale
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Introduction |
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Autosomal recessive juvenile parkinsonism is a distinct clinical and genetic entity first described in Japan in 1973. It is characterized by dystonia at onset, hyperreflexia, early complications from levodopa treatment (in contrast to dopa-responsive dystonia) and slow progression (Yamamura et al., 1973
). Mutations in parkin (PARK2, OMIM 602544), a gene that maps to chromosome 6q25–q27, were first identified in autosomal recessive juvenile parkinsonism (Kitada et al., 1998). Deletions and point mutations in the coding regions have been detected not only in kindreds with autosomal recessive juvenile parkinsonism of diverse ethnic origin but also in isolated young-onset parkinsonism and familial cases with an age of onset as late as 64 years (Abbas et al., 1999; Klein et al., 2000; Lucking et al., 2000). Parkin encodes a protein which functions as a ubiquitin-protein ligase through the C-terminal ring finger domain; mutants have impaired self-ubiquitination and impaired degradation of both self and synaptic vesicle-associated protein (Shimura et al., 2000; Zhang et al., 2000).
Neuropathology of parkin cases is limited but, in cases that have been reported, there was a severe and generalized loss of dopaminergic neurones in the substantia nigra pars compacta without Lewy body inclusions (Mori et al., 1998; Hayashi et al., 2000), implying that parkin disease is a pathological entity separate from idiopathic Parkinson’s disease (IPD) with overlapping clinical features. [18F]dopa PET examinations of parkin cases are limited (Broussolle et al., 2000; Hilker et al., 2001; Portman et al., 2001); however, subclinical nigrostriatal dysfunction has been demonstrated in carriers of a single mutant parkin allele (Hilker et al., 2001).
In 1991, an Irish kindred with young-onset levodopa-responsive parkinsonism was studied with [18F]dopa PET (Sawle et al., 1992). At that time, the four clinically affected siblings showed severely reduced [18F]dopa influx in striatum. Moreover, putamen [18F]dopa uptake was also mildly reduced in two asymptomatic members but normal in another asymptomatic sibling. Following the identification of parkin mutations causing early-onset parkinsonism in 1998 (Kitada et al., 1998), an affected individual in this kindred has been shown to be a compound heterozygote, having a deletion in exon 8 (C. Lucking, personal communication) and a splice site point mutation in intron 5 (M. Farrer, personal communication). This parkin family satisfied UK Brain Bank criteria for clinically probable Parkinson’s disease (Gibb et al., 1988) with rest tremor, dystonia and early complications as striking features. We have now repeated [18F]dopa PET, 10 years later, in all four clinically affected cases with parkin disease. We have also studied four asymptomatic relatives who carry a single parkin mutation and one sibling who has a normal genotype. Two of the parkin carriers and the relative with a normal genotype had serial [18F]dopa PET 7 years apart.
The aims were to study the rate of disease progression in clinically affected parkin cases and to assess the presence and possible changes with time of subclinical nigrostriatal dysfunction in carriers of a single parkin mutation.
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Patients and methods |
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Patients
Ten members of this family underwent a standardized neurological examination. A retrospective review of medical records and video material taken at the time of the first scan were used to estimate the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn et al., 1987
) and the Hoehn and Yahr (H&Y) score (Hoehn and Yahr., 1967) at the time of the first scan. Scores on the H&Y scale and the UPDRS scale in a practically defined ‘off’ state (12 h after withdrawal of medication) were used to rate the degree of parkinsonian disability at the time of the second scan. All subjects gave informed consent on both occasions, and the project was approved by the Joint Ethics Committee of the National Hospital for Neurology and Neurosurgery, London, UK.
PARK2 molecular analysis
Genomic DNA was extracted from peripheral white blood cells according to standard protocols. Parkin haplotypes were assigned using chromosome 6q25–q27 DNA markers D6S1550, D6S305, D6S411 and D6S253 (GenBank accession ID: 641523, 63059, 237957 and 62264, respectively). Samples were amplified using the polymerase chain reaction (PCR) and were analysed on a Perkin Elmer ABI 377 automated sequencer equipped with Genescan (version 3.1.2) software. Alleles were sized and assigned with Genotyper (v.2.5.1). All living family members were screened for the exon 8 deletion using semi-quantitative PCR methods previously described (Lucking et al., 2000). The PCR products were analysed on an ABI 377 automated sequencer using Genescan version 3.1.2 and Genotyper version 2.5.1 software (Applied Biosytems). The ratio of the peak heights of PCR products within the parkin gene were used to detect the presence of the deletion. Exon 5 of the parkin gene was amplified from genomic DNA by PCR using primers previously described (Kitada et al., 1998). Both strands were sequenced using a Big Dye Terminator Cycle Sequencing Ready Reaction DNA Sequencing kit (Applied Biosystems, Foster City, CA, USA), on an ABI 373 automated sequencer with the Sequence Analysis v.3.4.1 (Applied Biosytems) software.
Scanning protocol
At the time of the first scan, seven family members underwent [18F]dopa PET on a CTI 931 scanner (CTI/Siemens, Knoxville, TN, USA) with a reconstructed resolution of 1.5 cm as previously described (Sawle et al., 1992). The second scan was performed on an ECAT 966 scanner (CTI/Siemens, Knoxville, TN, USA) with a reconstructed resolution of 6 mm and included two additional family members as well as those scanned on the first occasion. Briefly, following a transmission scan obtained with an external 68Ge source, a mean dose of 129.5 MBq of [18F]dopa was injected as a bolus over 30 s and scanning was started at the onset of tracer infusion. All subjects gave prior written informed consent and were asked to stop their medication for 12 h before the PET scan. Permission to perform these studies was obtained from the Ethics Committee of the Hammersmith Hospitals Trust, London, UK and from the Administration of Radioactive Substances Advisory Committee (ARSAC), UK.
Region of interest analysis
Image analysis of all scans for each subject was performed using Analyze software (version 7.5, BRU, Mayo Foundation, Rochester, MN, USA) on SUN Sparc Ultra computer workstations. [18F]dopa uptake was expressed as an influx rate constant (Ki) and was calculated from caudate and putamen counts 25–95 min post-injection using multiple time graphical analysis with occipital tissue counts as a reference tissue input function (Brooks et al., 1990). A standard region of interest template was applied to parametric Ki images generated by in-house Kronos software (D. Bailey) written in IDL image analysis software (Research Systems, Inc., Boulder, CO, USA): each putamen was sampled with an elliptical region of 10 x 24 mm aligned along its axis, and each head of caudate with a circular region of 10 mm diameter. All regions of interest were placed by inspection with reference to the stereotactic atlas of Talairach and Tournoux (1988). For each patient, we measured caudate and putamen [18F]dopa Kis.
Because two different scanners were used over the 10-year period, [18F]dopa uptake was expressed as a percentage of the normal mean in healthy controls scanned with the respective scanners.
On the first occasion, 16 unrelated age-matched subjects (mean = 58.5 ± 14.3, range = 28–75 years) scanned on the CTI 931 scanner were used as controls. For the second scan, 14 unrelated, age-matched subjects (mean = 54.6 ± 13.9, range = 30–71 years) scanned on the ECAT 966 scanner with methods identical to those used for the parkin patients we used as controls. The controls reported no family history of parkinsonism and all had a normal neurological examination.
Seven patients with IPD, originally scanned on the 931 PET camera, with disease severity (evaluated on both clinical and [18F]dopa striatum uptake ground) similar to the parkin group at the time of their first scan, were re-scanned on the 966 PET scanner after an interval of 5.04 (±1.73) years between scans. The clinical characteristics of the parkin and IPD patients are detailed in Table 1.
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For those subjects who had repeat scans, the percentage annual rate of decline of [18F]dopa Ki (r) was calculated using the formula: r = [(mean Ki for the group of healthy controls – subject Ki)/mean Ki of the group of healthy controls]/number of years between consecutive scans) x 100.
Statistical analysis
The non-parametric Wilcoxon test was used for all comparisons between different groups of patients and controls.
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Results |
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Clinical data for affected patients
Our parkin kindred originated from a small village in Southern Ireland. There was no known parental consanguinity and the parents did not have parkinsonism. The affected cases fulfilled the clinical diagnostic criteria of the UK Parkinson’s Disease Society Brain Bank for Parkinson’s disease except for the presence of a family history (Gibb et al., 1988
). Four (one female and three males) out of 10 siblings were affected at the time of the study in 1990 and no further members of this kindred have developed the disease. The mode of transmission was consistent with autosomal recessive inheritance. Mean age of onset of symptoms was 29 years (range 28–32 years). All affected siblings had a striking response to L-dopa therapy, with levodopa-related dyskinesias after a mean interval of 2.4 years. Estimated mean clinical disease duration was 26 years (range 19–32 years) at the time of the second scan. The clinical presentation of the patients was comparable with that of juvenile-onset parkinsonism; however, currently their phenotype was indistinguishable from IPD, with a common feature of severe resting leg tremor (abduction–adduction oscillations).
Patient III.1
This 60-year-old man reported initial symptoms of fatigue, lower limb pain and slowness from the age of 28 years, with subsequent turning in of both feet. At the time of the first scan, he was H&Y stage II with a UPDRS ‘off’ score of 39. Following a 10-year interval, at the time of the second scan, disease duration was 32 years and he had now reached H&Y stage III and an UPDRS off score of 59. In the ‘off’ state, he had a predominant abducting–adducting oscillatory tremor of both lower limbs at rest, with asymmetrical bradykinesia and rigidity (left more than right). His posture was upright and he was unsteady on his feet. He had been receiving L-dopa for 14 years and continued to report a significant improvement taking 1000 mg a day albeit with moderate inter-dose dyskinesia and severe motor fluctuations. He was able to walk up to 3 miles at a time and maintain a job as a local handyman.
Patient III.4
This 55-year-old man reported initial symptoms of slowness, right leg tremor and involuntary inversion of both feet from the age of 27 years. At the time of the first scan, he was H&Y stage II with a UPDRS ‘off’’ score of 57. Following an 11-year interval, at the time of the second scan, disease duration was 29 years and he had progressed to H&Y stage IV and a UPDRS ‘off’ score of 108. In the ‘off’ state, he had a severe abducting–adducting oscillatory tremor of both lower limbs at rest, with symmetrical bradykinesia and rigidity, postural instability and poor arm swing. At the time of the second scan, he had been on L-dopa therapy for 23 years and continued to report significant improvement and dyskinesias with L-dopa, taking 1200 mg a day. He was, however, no longer able to continue with employment as a landscape gardener; his disability had been exacerbated by lumbar canal stenosis such that he required walking sticks and, at times, a wheelchair.
Patient III.5
This 54-year-old housewife reported symptoms of slowness, leg pain and leg tremor from the age of 31. At the time of the first scan, she was H&Y stage II and her UPDRS ‘off’ score was 42. Following an 11-year interval, at the time of the second scan, disease duration was 19 years and she had progressed to H&Y stage IV and a UPDRS ‘off’ score of 74. She had considerable motor fluctuations, with her ‘off periods’ being characterized by marked generalized stiffness, pain, bilateral resting leg tremor, shuffling gait and poor balance such that she was barely able to mobilize independently and perform activities of daily living. She had been on L-dopa for 11 years and continued to report a significant improvement from L-dopa taking 500 mg a day, but had developed motor fluctuations and dyskinesias.
Patient III.8
This 51-year-old former builder reported initial symptoms of bilateral leg tremor and involuntary inversion of the right foot from the age of 32. At the time of the first scan, he was H&Y stage II with a UPDRS ‘off’ score of 59. He developed inter-dose painful dystonic cramps of the feet and severe chorea of the head, trunk and legs. Following an 11-year interval, disease duration was 19 years at the time of the second scan and he had progressed to H&Y stage IV and a UPDRS ‘off’ score of 90. ‘Off’ periods were associated with fatigue and distressing rest tremor of the legs and to a lesser degree the arms. Rigidity and bradykinesia were worse in the legs. At the time of the second scan, he had been receiving L-dopa therapy for 18 years and continued to report a significant improvement, taking 1200 mg a day.
Clinical data for asymptomatic cases
None of the carriers of a single parkin mutation reported any symptoms.
Individual IV.1
This individual was first examined at the age of 19 years and then had [18F]dopa PET when she was 24 and again when she was 30. At 19 years of age, she had a postural tremor of the right arm. At follow-up, 11 years later, there was a postural tremor of both hands (right more than left), rest tremor of both legs and reduced arm swing on the right. Tone was normal with no evidence of bradykinesia, hypomimia or micrographia. Despite these extrapyramidal signs, the UK Brain Bank diagnostic criteria for Parkinson’s disease (Gibb et al., 1988) were not fulfilled.
Individual III.2
This subject, a housewife, had a normal examination in 1990 but at the time of the second scan had facial masking and reduced left arm swing.
Individual III.3
This individual was also a housewife, and had a history of diabetes, depression and schizophrenia that had been treated previously with chlorpromazine. Present treatment for depression included olanzapine, procyclidine and sertraline. Clinical examination at the time of the first scan was normal, but at follow-up there was a positive glabellar tap with normal tone, poor arm swing and mild paucity of facial expression with a bucco-lingual masticatory syndrome and stereotypies of the lower limbs.
Individuals III.3, III.7, III.11
The neurological examination of individual III.11 was normal. Of those siblings with a normal genotype, individual III.7 had a normal neurological examination. Individual II.3, a 75-year-old paternal uncle, was not examined on the second occasion nor scanned on either occasion.
Molecular data
Haplotype analysis in the region of parkin showed evidence of linkage (Fig. 1). A deletion in exon 8 was identified in a paternal uncle II.3 and siblings III.1–5 and III.8. These cases were hemizygous for alleles at marker D6S411, confirming the presence of a deletion in exon 8 and segregating with the paternal haplotype 4-3-x-1. The second mutation, an intron 5 +2 T
A splice mutation, was detected in the mother, II.5, siblings III.1, III.4, III.5, III.8, III.10 and III.11, and offspring IV.1, and segregated with the maternal haplotype 1-3-2-1. The clinically affected individuals were compound heterozygotes, having an exon 8 deletion and an intron 5 +2 TA splice mutation and shared heterozygous haplotypes 4-3-x-1 and 1-3-2-1. Of the asymptomatic cases, three carried a paternally inherited parkin-associated haplotype (II.3, III.2 and III.3) and a detectable exon 8 mutation, and one sibling (III.10), one half-sibling (III.11) and one offspring (IV.1) inherited the maternal parkin-associated haplotype and a detectable intron 5 +2 TA splice mutation. Siblings III.7 and III.9 did not inherit either of the parkin-associated haplotypes and did not have an exon 8 deletion or an intron 5+2 TA splice site mutation. Haplotypes are shown in Fig. 1.
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PET data
Mean values for [18F]dopa caudate and putamen uptake, expressed as percentage reduction relative to the normal mean, at the first and second scan for the parkin and the IPD groups are shown in Table 2.
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At the time of the first scan, percentage reductions below the normal mean in caudate [18F]dopa uptake in the parkin and IPD groups were not significantly different (55 ± 12 versus 43 ± 5, P = 0.109); similarly, putamen percentage reductions below the normal mean were not significantly different in the two groups (64 ± 4 in the parkin versus 58 ± 8 in the IPD patients, P = 0.315) (Table 2).
Figure 2 shows the individual rates of decline in putamen [18F]dopa uptake relative to the normal mean for the four parkin patients and the seven IPD patients. The mean percentage rate of decline of putamen [18F]dopa uptake relative to the normal mean was 1.47% (±0.5) per annum for the parkin group and 5.71% (±1.63) per annum for the IPD group. The rates of progression between these two groups was significantly different (P = 0.0008) (Fig. 3).
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The mean percentage rate of decline of caudate [18F]dopa uptake relative to the normal mean was 1.72% (±1.7) per annum in the parkin group and 3.51% (±1.04) per annum in the IPD group. This difference was not statistically significant (P = 0.885).
Within the parkin group, the mean percentage rate of decline in caudate was not significantly different from that of putamen (1.72 ± 1.7 and 1.47 ± 0.5, respectively, P = 0.16), while within the IPD group the mean percentage rate of decline was significantly slower in the caudate than in the putamen (3.51 ± 1.04 and 5.71 ± 1.63, respectively, P = 0.006).
Clinically asymptomatic cases
Sibling III.7, who had a normal genotype, had normal caudate and putamen [18F]dopa uptake (Table 3) which remained normal after 6 years. Individually, two parkin carriers showed low normal levels of caudate Ki (>1.5 SDs below the normal mean) and three carriers had a low normal putamen Ki (>1.5 SDs below the normal mean) (Table 3).
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As a group, the four carriers had significantly reduced mean caudate and putamen [18F]dopa uptake (0.0119 ± 0.00047 and 0.0117 ± 0.00054, respectively) compared with that of the healthy controls (0.0153 ± 0.0026 and 0.0168 ± 0.0031, respectively) (P = 0.0126 and 0.009, respectively) (Fig. 4).
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Two of the carriers (III.3 and IV.1) were scanned on two occasions (after 9 and 6 years, respectively). The rate of changes in caudate and putamen [18F]dopa uptake per annum was 0.14 and 0.09%, respectively, in carrier III.3, and 0.73 and 0.74%, respectively, in carrier IV.1.
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Discussion |
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We have used serial [18F]dopa PET to measure over a 10-year period the rate of loss of dopaminergic function in clinically affected members of a kindred with parkin disease. The mean annual loss of putamen [18F]dopa Ki relative to the normal mean was 1.48 % in parkin disease compared with 5.71% in the group with IPD, suggesting that disease progression in established parkin disease is slower. Our findings for IPD patients are in agreement with previous studies which have reported a mean annual 6% loss of putamen [18F]dopa storage relative to the normal mean or 12% relative to patient baseline (Morrish et al., 1996
). Although our IPD group were not age matched with the parkin patients, their duration of clinical symptoms at the time of the baseline scan was not significantly different and they had a severity of disease similar to that of the parkin group, as evidenced by similar reductions of putamen [18F]dopa uptake and motor scores. Similar severity and duration of disease at baseline rather than age are the critical factors when assessing rate of progression of Parkinson’s disease in two groups of patients since [18F]dopa striatal uptake per se is not influenced by age (Sawle et al., 1990; Eidelberg et al., 1993). The rate of decline of putamen uptake amongst the symptomatic parkin patients was similar, whilst we observed some variability in the rate of decline of caudate uptake. However, mean caudate Ki deteriorated at approximately the same rate as mean putamen Ki in the parkin group, whereas in the IPD group caudate dopamine function was relatively spared at baseline and deteriorated at a slower rate than putamen. The finding that nigrostriatal dysfunction in parkin disease progresses more slowly than IPD is in keeping with the clinical observation that cases of young-onset parkinsonism can have a normal life span, and suggests that neurodegeneration in parkin disease is an indolent process.
Intra-sibling variability of both Ki values and degree of parkinsonian disability amongst clinically affected cases may be due to the influence of other unlinked genes (modifier genes) and undefined environmental influences. Generally, however, the pattern and course of the affected cases were remarkably similar.
Because of the lapse of time, >10 years, we had to use two different PET cameras. We acknowledge that the procedure is not rigorous. We compensated for this by normalizing patient data to control groups scanned with the respective scanners and by matching a group of IPD patients with similar disease severity and duration of clinical symptoms to that of the parkin group at the time of the first baseline scan. Our sample size was small and confined to a single family such that the rate and pattern of nigral cell loss that we found may be specific to this family. Our results require confirmation with a larger study.
In this study, we also observed dopaminergic dysfunction in the group of asymptomatic parkin carriers. Abnormal nigrostriatal function in heterozygous carriers (clinically asymptomatic cases with a single mutant allele) may be attributed to haplo-insufficiency (Strachen et al., 2000) such that a single mutant allele results in a reduction of up to 50% of ubiquitin ligase activity, which may not be sufficient for normal nigrostriatal activity. This would imply that the ligase activity of the parkin gene product is dosage sensitive, and that sufficient relative levels of enzyme are required for interaction with other gene products of the ubiquitin-conjugating pathway. The effects of modifying genes particularly influence those cases in which the phenotype is dependent on haplo-insufficiency and environmental factors (Strachen et al., 2000). An alternative explanation is a dominant-negative effect (Strachen et al., 2000); the non-functional mutant parkin polypeptide physically interferes with the function of the normal polypeptide, suggesting that dimerization or oligomerization of the protein is requisite for normal function. Moderate reduction in protein function caused by either haplo-insufficiency or a dominant-negative effect may produce nigrostriatal damage in heterozygous carriers. An alternative explanation is that the [18F]dopa PET changes observed are of no clinical significance; however, the manifestation of subtle extrapyramidal signs in three parkin carriers (one of whom, however, had a history of neuroleptic exposure) suggests that these individuals may well be ‘manifesting heterozygotes’ and raises the possibility that they may be at risk of developing parkin disease. Severe reduction, however, in ubiquitin ligase activity in homozygotes may produce the recessive condition, which results in marked nigrostriatal dysfunction and the clinical disease.
In the two carriers of a single parkin mutation, scanned 9 and 6 years apart, there were no significant changes in [18F]dopa uptake with time, similar to their sibling with normal genotype (III.7) and to what is seen in normal volunteers (Morrish et al., 1996). This implies that either the two carriers have a fixed deficit that does not progress with time or the rate of nigral cell death was too slow to be detected with PET over the time period. Alternatively, there may also be additional pathophysiological processes at the postsynaptic receptor not detectable by [18F]dopa PET. The clinical development of mild signs of basal ganglia dysfunction between the two examinations is, however, intriguing and suggests incipient nigral cell dysfunction. Repeated observations with clinical examination and repeat scanning over time in a much larger cohort will be necessary to confirm these findings.
Conclusions
Clinically affected cases with parkin mutations showed significantly slower progression of putamen dopamine terminal dysfunction, as evidenced by [18F]dopa PET findings, compared with late-onset IPD patients. Nigrostriatal dopaminergic dysfunction was found in a group of four asymptomatic heterozygous parkin carriers from the same family, three of whom manifested subtle extrapyramidal signs.
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Acknowledgements |
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We wish to thank colleagues Peter Dixon and Elizabeth Graham in the Neurogenetics Unit, Institute of Neurology, for helpful discussions; Christoph Lucking and Alexis Brice at the Hopital de la Salpetriere, Paris, Matt Farrer at the Mayo Clinic, Florida, and colleagues at the MRC Clinical Sciences Centre, Radiochemistry and Methods Section whose expertise made these studies possible; Hope McDevitt, Stella Ahier and Andrew Blyth for their expert help with scanning; Guy Sawle and Stephen Wroe for providing helpful comments; and Sister Margaret Lynch for her invaluable help in liaising with family members. N.L.K. is funded by the Parkinson’s Disease Society and the Brain Research Trust.
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