European Journal of Nuclear Medicine and Molecular Imaging

, Volume 32, Issue 12, pp 1452–1456

The effect of levodopa therapy on dopamine transporter SPECT imaging with 123I-FP-CIT in patients with Parkinson’s disease

Authors

    • Department of Biopathology and Diagnostic ImagingUniversity Tor Vergata
  • Mariangela Pierantozzi
    • Department of Neurological SciencesUniversity Tor Vergata
    • Santa Lucia Foundation I.R.C.C.S.
  • Luca Filippi
    • Department of Biopathology and Diagnostic ImagingUniversity Tor Vergata
  • Carlo Manni
    • Department of Biopathology and Diagnostic ImagingUniversity Tor Vergata
  • Livia Brusa
    • Department of Neurological SciencesUniversity Tor Vergata
    • Santa Lucia Foundation I.R.C.C.S.
  • Roberta Danieli
    • Department of Biopathology and Diagnostic ImagingUniversity Tor Vergata
  • Giorgio Bernardi
    • Department of Neurological SciencesUniversity Tor Vergata
    • Santa Lucia Foundation I.R.C.C.S.
  • Giovanni Simonetti
    • Department of Biopathology and Diagnostic ImagingUniversity Tor Vergata
  • Paolo Stanzione
    • Department of Neurological SciencesUniversity Tor Vergata
    • Santa Lucia Foundation I.R.C.C.S.
Original Article

DOI: 10.1007/s00259-005-1922-9

Cite this article as:
Schillaci, O., Pierantozzi, M., Filippi, L. et al. Eur J Nucl Med Mol Imaging (2005) 32: 1452. doi:10.1007/s00259-005-1922-9

Abstract

Purpose

The aim of this study was to evaluate, by means of 123I-FP-CIT SPECT, the effect of chronic treatment with levodopa on striatal dopamine transporter (DAT) in patients with Parkinson’s disease.

Methods

Fifteen patients under stable levodopa/carbidopa monotherapy were imaged twice: at baseline on medication and after at least 20 days of treatment wash-out. DAT levels were assessed from SPECT imaging for the entire striatum, the right and left striatum, the right and left putamen and the right and left caudate, as a ratio of regional brain activities using the formula: (striatal region of interest−occipital)/occipital.

Results

During levodopa wash-out, despite a worsening in patients’ clinical disability (H&Y mean stage 2.53±0.58 versus 1.73±0.45 on therapy, p<0.001), striatal 123I-FP-CIT levels were not significantly different from those at baseline in any of the brain regions examined.

Conclusion

The results of this study suggest that levodopa does not affect 123I-FP-CIT brain imaging and confirm that it is not necessary to withdraw this medication to measure DAT levels with SPECT.

Keywords

Parkinson’s diseaseDopamine transporter123I-FP-CITLevodopaSPECT

Introduction

Imaging of dopamine transporter (DAT) using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) has been proved to be a useful diagnostic method for the evaluation of patients with movement disorders [13]. Several SPECT studies have demonstrated high accuracy in differentiating patients with Parkinson’s disease (PD) and parkinsonian syndromes from patients with essential tremor and healthy controls [1, 2]. The 123I DAT ligand N-ω-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl)nortropane (123I-FP-CIT) is increasingly used because it is commercially available and, due to its fast kinetics, it allows early imaging [4]. 123I-FP-CIT striatal uptake is reduced in PD, and SPECT results correlate with both disease duration and severity [5]. Therefore, 123I-FP-CIT imaging could be a useful tool to monitor PD progression, if its striatal binding is not affected by the medication used to treat patients.

Previous studies using the DAT radioligand 123I-β-CIT have demonstrated that antiparkinsonian therapy would have no significant effect on its striatal uptake [6, 7]. Based on these findings indicating that dopamine and dopamine agonists in standard dosages do not markedly affect DAT binding, patients are currently submitted to SPECT study without withdrawing these drugs [8]. Nevertheless, to our knowledge, there have been no previous investigations on the effect of chronic treatment with levodopa on striatal DAT imaging in patients with PD using 123I-FP-CIT as a radiopharmaceutical. A prior study in rats evaluated the effect of acute and sub-chronic administration of several dopaminergic medications on 123I-FP-CIT striatal binding [9]. Radioactivity concentrations in the striatum after the rats had been killed were not statistically significantly different from those in controls after either acute or sub-chronic dopamine administration. The results of this animal study suggested that it would most likely be unnecessary to interrupt dopamine treatment before 123I-FP-CIT imaging.

In the current study, we evaluated whether chronic levodopa therapy influences 123I-FP-CIT striatal uptake in patients with PD, to verify that in vivo imaging in humans confirms the findings previously observed in rat brain.

Materials and methods

Patients

Fifteen patients (seven females and eight males aged 58–77 years) affected by a prevalent rigid-akinetic form of idiopathic PD, diagnosed according to the Parkinson’s Disease Society Brain Bank criteria [10], were recruited from the movement disorder outpatient clinic. Exclusion criteria were the presence of cerebral lesions on computed tomography or metabolic disorders; moreover, patients treated with antiparkinsonian drugs (i.e. dopamine agonists, anticholinergics, selegiline) other than levodopa therapy or using benzodiazepines or any other neuroactive drug were not included. Patients underwent an accurate neurological examination and their clinical disability was quantified by the motor examination section of the Unified Parkinson Disease Rating Scale (UPDRS-III), while the stage of PD was assessed using the Hoehn and Yahr (H&Y) scale [11, 12].

Patients’ demographic and clinical features are summarised in Table 1. They were levodopa responsive and none of them experienced motor fluctuation or disabling levodopa-induced dyskinesias under stable levodopa/carbidopa monotherapy at a daily dose from 400 to 800 mg. Ten patients used a combined treatment including regular and controlled-release drug formulations, while the other five were taking regularly released levodopa/carbidopa exclusively.
Table 1

Patients’ demographic and clinical features

Patient no.

Age (years)

Gender

Disease duration (months)

Levodopa therapy duration (months)

Total daily dose of levodopa (mg)

H&Y stage

UPDRS-III

On therapy

Off therapy

On therapy

Off therapy

1

73

M

54

48

750

2.0

2.5

21

32

2

64

M

30

24

500

2.0

3.0

14

30

3

66

M

72

60

800

1.5

3.0

13

51

4

71

F

48

24

550

2.0

2.5

19

30

5

69

M

24

14

400

1.0

1.5

8

20

6

72

M

60

48

600

2.0

3.0

24

49

7

58

F

54

10

450

1.5

2.5

10

23

8

75

F

24

18

650

2.0

3.0

19

49

9

76

F

36

12

500

2.0

2.5

20

36

10

77

F

58

48

550

1.5

2.5

12

34

11

59

M

72

36

700

2.0

3.0

24

48

12

66

F

80

60

750

2.0

3.0

22

45

13

62

M

24

12

550

1.0

1.5

9

19

14

66

F

24

12

500

1.0

1.5

7

18

15

72

M

60

48

750

2.5

3

31

42

Mean

68.40

 

48.00

31.60

600

1.73

2.53

16.80

35.06

SD

±5.99

 

±19.65

±18.77

±125.35

±0.45

±0.58

±7.04

±11.77

F female, M male, SD standard deviation

All the patients were submitted to two 123I-FP-CIT SPECT studies within 6 weeks. At the time of the first SPECT study they were on levodopa treatment. Then, they stopped the antiparkinsonian therapy for assessment of disease progression, independently of the purpose of this study, and a second SPECT examination was conducted after complete pharmacological wash-out for at least 20 days. UPDRS-III and H&Y clinical assessments were carried out immediately before each scintigraphic examination. All the patients gave their informed consent to enter the study and the local ethics committee approved the procedures.

SPECT imaging

Each patient was i.v. injected with 185 MBq of 123I-FP-CIT (Amersham Health, UK) that was given at the same time of the day and under the same experimental conditions. Perchlorate (1,000 mg) was administered at least 30 min before radiopharmaceutical injection to block thyroid uptake of free radioactive iodide [8].

Imaging were always performed 4 h after 123I-FP-CIT using a dual-head gamma camera (Millennium VG; General Electric Medical Systems, Milwaukee, WI), equipped with low-energy high-resolution collimators. SPECT studies were acquired using the following parameters: 128×128 matrix, 120 projections (rotation of 360°), 40 s per projection. The slice thickness was 4.42 mm. Reconstruction was performed by filtered back-projection with a Butterworth filter (cut-off frequency 0.5, order 10) to produce transaxial slices that were attenuation corrected. Attenuation correction was performed according to Chang’s method [13] using a coefficient μ=0.11 cm−1, after manually drawing an ellipse around the head contour.

For analysis of 123I-FP-CIT striatal uptake, the ratio of specific to non-specific binding was calculated by summing the three adjacent transverse slices that showed the most intense striatal uptake. The slices were reoriented to be parallel to the canthomeatal line. A standard ROI template, constructed manually according to a stereotactic atlas as previously described by Booij et al. [4] and including fixed regions for both putamina, caudate nuclei and occipital cortices, was placed on the summed images. Small variations in the individual brain required movement of the ROIs within the template, without changing their size or shape, for optimal positioning. Therefore, the exact same ROIs were used in all patients for both images. The ratio of specific to non-specific binding was then calculated as 123I-FP-CIT binding=(ROI−O)/O, in which ROI represents the mean counts in the region of interest (putamen or caudate nucleus) and O represents the mean counts in the occipital cortex. The average striatal ROI activity was calculated for the entire striatum, left striatum and right striatum as the size-weighted average of the right and left putamen and caudate activities. The percentage change in the specific striatal 123I-FP-CIT uptake ratios in the various regions between the two SPECT studies was also assessed. Moreover, the change in non-specific occipital uptake was evaluated.

Statistical analysis

The two-tailed paired Student’s t test was used to analyse differences in 123I-FP-CIT striatal uptake in individual regions between scans performed with the patient on medication and following withdrawal. The clinical data were similarly analysed. For all analyses, p<0.05 was considered statistically significant.

Results

The PD patients’ H&Y mean stage on therapy was 1.73±0.45, while it was 2.53±0.58 during levodopa withdrawal (p<0.001). The clinical disability (assessed by the UPDRS-III motor examination) on and off levodopa therapy was 6.8±7.0 and 35.06±11.7, respectively (p<0.001). Therefore, levodopa wash-out produced a significant worsening of patients’ clinical stage and motor disability at clinical evaluation in comparison to the baseline condition on therapy. However, all patients tolerated the drug withdrawal well, and none encountered clinically considerable adverse effects during the wash-out period.

No serious adverse events were recorded after 123I-FP-CIT injection. Table 2 summarises the scintigraphic results. No patient had normal SPECT imaging (i.e. without evidence of a dopaminergic deficit in the striatum) either during therapy or after levodopa withdrawal. The mean 123I-FP-CIT striatal uptake was statistically similar (p=0.75) on therapy (1.84±0.40) and after levodopa wash-out (1.80±0.34). The lack of effect of treatment withdrawal on 123I-FP-CIT striatal uptake was also confirmed by our analysis in the different regions considered: in none of them was a statistically significant variation found between the two studies. In particular, no significant difference was observed when caudate and putamen (both right and left) were also individually evaluated (Fig. 1).
Table 2

Summary of the results

Striatal to non-specific uptake ratios

On therapy (mean±SD)

Off therapy (mean±SD)

P value

Percent change

Entire S/O

1.84±0.40

1.80±0.34

0.75

−2.1

Right S/O

1.59±0.35

1.55±0.31

0.78

−2.5

Left S/O

1.56±0.36

1.55±0.33

0.91

−0.6

Right C/O

1.94±0.42

1.86±0.33

0.58

−4.1

Left C/O

1.91±0.48

1.87±0.37

0.77

−2.0

Right P/O

1.61±0.40

1.60±0.35

0.95

−0.6

Left P/O

1.57±0.33

1.58±0.34

0.97

+0.6

S/O striatal to non-specific uptake ratio, C/O caudate nucleus to non-specific uptake ratio, P/O putamen to non-specific uptake ratio; SD standard deviation

Fig. 1

Patient 9. 123I-FP-CIT SPECT images on levodopa therapy (left) and off therapy (right): there is no significant difference in DAT striatal binding between the studies

Moreover, levodopa wash-out did not induce a significant change in occipital (i.e. non-specific) uptake of 123I-FP-CIT (SPECT on medication versus SPECT after therapy withdrawal: p=0.53).

Discussion

The role of neuroimaging techniques, including SPECT, in assessing neuroprotective therapies in PD is still under debate [14, 15]; however, to be useful for this purpose, imaging should not be influenced by the drugs used to treat patients. The findings of previous PET studies in early PD patients after treatment with levodopa are discordant: Guttman et al. [16] reported a significant reduction of DAT binding in all striatal regions after 6 weeks of therapy, whereas Nurmi et al. [17] did not observe any significant effect after 3 months of treatment.

Lavalaye et al. [9] evaluated 123I-FP-CIT binding in rat brain after acute and sub-chronic administration of various medications, including dopaminomimetics, antipsychotics and an antidepressant. They found only small and not statistically significant changes in absolute 123I-FP-CIT striatum binding and in striatum/cerebellum binding ratio after both acute and sub-chronic administration of sinemet or pergolide. Based on these results, it was concluded that dopaminergic therapy would not affect DAT imaging with 123I-FP-CIT in humans, and so dopaminergic medication would not necessarily have to be withdrawn prior to SPECT using this radiopharmaceutical. Nevertheless, although all drugs were administered in a quantity higher than the usual therapeutic human doses, it is difficult to extrapolate from this animal study definitive conclusions regarding the possible influence of anti-parkinsonian medication on 123I-FP-CIT imaging in humans.

The effects of sub-chronic treatment with up to 750 mg levodopa/carbidopa daily on striatal 123I-β-CIT uptake was assessed by Innis et al. [6]. Eight patients, who had never been previously treated with levodopa, were submitted to three SPECT studies: at baseline, on medication after 6 weeks of therapy and after 1 week of levodopa discontinuation. Total striatal uptake levels were not significantly different among the three measurements; moreover, no important effects were found when putamen and caudate ROI values were separately analysed (data not shown), and also significant changes in occipital uptake were not observed when comparing any of the three SPECT studies. In addition, no effects on DAT SPECT were found in a different group of eight PD patients treated with levodopa and imaged three times: at baseline, after 1 month of therapy with 10 mg selegiline daily and 9 weeks after selegiline withdrawal. These results clearly indicate that sub-chronic therapy with levodopa/carbidopa or selegiline does not induce significant modulation of striatal DAT levels, and therefore patients can be studied with 123I-β-CIT SPECT without withdrawing these medications.

No significant change in 123I-β-CIT uptake was also observed in six patients of the CALM-PD-CIT study, after a 10-week dosage escalation period of levodopa treatment [18].

In a recent multicentre clinical trial aimed at assessing the effect of levodopa on the course of PD, 123I-β-CIT imaging was performed in a subset of 135 patients with early PD [19]. SPECT was acquired at baseline (with patients receiving no antiparkinson medication) and at week 40, after subjects had been randomly assigned to receive placebo or levodopa/carbidopa (150–600 mg/day). The percent decrease in striatal uptake after treatment was greater in the levodopa group than in the placebo one, but the difference was not statistically significant; nevertheless, after excluding subjects with a normal baseline SPECT, this difference in reduction became significant. However, no decrease in striatal uptake was observed in the 16 subjects with a normal baseline SPECT who received levodopa. Based on these findings, and in the absence of studies with a longer period of levodopa therapy, the authors could not exclude the possibility that levodopa might down-regulate the DAT.

In the present study, we used 123I-FP-CIT to verify that chronic levodopa therapy is really unable to modulate DAT levels in humans, i.e. in the striatum of PD patients with a mean therapy duration of 31.6 months. Our results indicate that chronic levodopa therapy does not cause significant occupancy of the DAT binding sites labelled with 123I-FP-CIT. These findings are in accordance with prior observations with DAT SPECT tracers [7, 10, 19]: in human studies, however, 123I-β-CIT was used and only PD patients receiving sub-chronic (6–10 weeks) levodopa therapy were investigated.

Clinical response to levodopa consists of two basic components characterised by a different temporal profile: the short duration response, which lasts a few hours after a single levodopa dose and is directly related to the drug pharmacokinetics, and the long duration response (LDR), which is a sustained motor benefit derived from the continued levodopa treatment [20, 21]. The LDR is interesting since it does not parallel the levodopa plasma concentrations, but builds up over days and lasts days to weeks after therapy is stopped [2123]. Since the LDR has been considered to correspond to one-third to one-half of the therapeutic response in chronically treated PD patients [24], in our study the second DAT SPECT was carried out after a therapy withdrawal sufficient to ensure no significant LDR interference. The opportunity to perform such a SPECT study arose in patients who were completing a 20-day wash-out from chronic levodopa treatment in order to assess the progression of the underlying disease by measuring changes in clinical status. Prolonged levodopa wash-out (from 1 to 4 weeks) has been used for this purpose in clinical trials [2527]. Although in the majority of studies a 2-week withdrawal has been adopted, Hauser and Holford [22], using a modelling technique, have recently suggested that a period of 32 days may be theoretically required to remove approximately 90% of the long-term clinical benefit of levodopa. On the basis of these data, a 20-day withdrawal was selected as a realistic, well-tolerated wash-out period sufficiently long to eliminate the LDR substantially, allowing real clinical assessment of the severity of PD progression without significant discomfort for the patients, and to perform the second SPECT study.

We evaluated the possible effects of levodopa on both the entire striatum and the putamen and caudate, which are commonly affected in a different way in PD, with putamina usually showing a more severe DAT loss [1, 28]. Moreover, we separately analysed 123I-FP-CIT uptake in the different regions (striatum, caudate and putamen) of the right and the left side. By comparison, Innis et al.’s results [6] were obtained in the entire striatum, without showing data on individual putamen and caudate assessment, even though they stated that the separate analysis of uptake in these nuclei also did not show any effect.

In all the different regions we found that levodopa did not significantly affect 123I-FP-CIT uptake, clearly indicating that this chronic treatment does not interfere with striatal DAT imaging of this radiopharmaceutical, whose measurements were found to be reliable and reproducible both in healthy controls and in PD patients under levodopa treatment in a test–retest study [29]. However, it is worth highlighting that we evaluated only patients with mild and moderate PD; in fact, in patients at more severe stages, pharmacological wash-out tests could be difficult, and there are reasonable ethical concerns. Consequently, our findings cannot be generalised to patients with severe stage PD, who were not included in this series.

In conclusion, the results of our study suggest that chronic levodopa therapy does not cause significant occupancy of the DAT binding site labelled with 123I-FP-CIT within striatum, putamen or caudate, and therefore it does not affect the results of DAT imaging with this radiopharmaceutical in patients with mild and moderate PD. These findings confirm (a) that it is not necessary to withdraw levodopa before performing 123I-FP-CIT SPECT, which is important because interruption of medication may cause dramatic worsening of patients’ symptoms, and (b) the validity of DAT imaging for monitoring disease progression in PD patients treated with this therapy. Further studies in larger series are necessary to definitively confirm our data, if possible also in patients with severe PD, and to evaluate in vivo the potential effects of other antiparkinsonian drugs on 123I-FP-CIT DAT imaging.

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© Springer-Verlag 2005