Presymptomatic diagnosis of experimental Parkinsonism with 123I-PE2I SPECT

NeuroImage 19 (2003) 810 – 816

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Presymptomatic diagnosis of experimental Parkinsonism with 123I-PE2I SPECT Caroline Prunier,a,* Erwan Be´zard,b Je´roˆme Montharu,c Marina Mantzarides,a Jean-Claude Besnard,a Jean-Louis Baulieu,a Christian Gross,b Denis Guilloteau,a and Sylvie Chalona a

b

INSERM U316, Laboratoire de Biophysique me´dicale et Pharmaceutique, 31 avenue Monge, 37200 Tours, France Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Universite´ Victor Segalen, 146 rue Le´o Saignat, 33076 Bordeaux Cedex, France c Plateforme Pluri-Formation Animalerie, CHU Bretonneau, 2 boulevard Tonnelle´, 37044 Tours Cedex, France Received 10 June 2002; revised 10 October 2002; accepted 12 November 2002

Abstract Presymptomatic diagnosis of the loss of nigrostriatal neurons that characterises Parkinson’s disease, is a crucial issue for future neuroprotective therapies as degeneration exceeds 70 to 80% when symptoms appear. Here we propose an early diagnosis method that utilises single photon emission computerized tomography (SPECT) coupled to the iodine-123-labelled selective dopamine transporter ligand N-(3-ioprop-2E-enyl)-2-␤-(4-methylphenyl)nortropane (123I-PE2I), applying Logan’s graphical method for quantification. Sequential 123IPE2I SPECT acquisitions were performed in nonhuman primates chronically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that consistently produces a progressive Parkinsonian state. While classical neurological examination only allows detection of Parkinsonian signs at Day 12 of the protocol of intoxication, the mean distribution volume ratio calculated according to Logan’s graphical method is significantly decreased from Day 6 onward, i.e., when animals are clinically normal. 123I-PE2I SPECT is a very sensitive method to detect presymptomatic lesions of nigrostriatal neurons and the first to be experimentally validated. It could now be used clinically for early diagnosis and follow-up of neuroprotective treatment. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Lesion progression; Monkey; Parkinson’s disease; SPECT; Dopamine transporter; Logan’s quantification

Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder that occurs in 1% of the population over 55, the mean age at which the disease is first diagnosed (Hoehn and Yahr, 1967). PD consists of a syndrome including tremor, rigidity, postural abnormalities, and bradykinesia. The two principal pathological characteristics of PD are the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (Hassler, 1938) and a ventrocaudal

* Corresponding author. Present address: Service de Me´decine Nucle´aire, CHU Bretonneau, 2 boulevard Tonnele´, 37044 Tours Cedex, France. Fax: ⫹33-247-473-876. E-mail address: [email protected] (C. Prunier).

gradient in degenerative lesion progression (Ehringer and Hornykiewicz, 1960). Whereas the aetiology underlying clinical deterioration remains unknown, PD is characterised by its progressiveness (Hoehn and Yahr, 1967). It has been suggested that progression of symptoms in PD is the consequence of linear age-related cell attrition superimposed upon substantia nigra compacta already damaged by transient exposure to a previous insult (Koller et al., 1991). An alternative view is that the onset and progression of idiopathic PD represents a novel ongoing degenerative process (McGeer et al., 1988) with an exponential decay (Fearnley and Lees, 1991). While the length of the period preceding the first appearance of clinical signs remains open to debate, it is generally accepted that Parkinsonian signs appear when dopaminergic neuronal death exceeds a critical threshold, 70 – 80% of

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striatal nerve terminals and 50 – 60% of SNc perikarya (Bernheimer et al., 1973; Riederer and Wuketich, 1976). The implications of this concept are substantial given that it defines a period in which DA depletion progresses without symptoms. This presymptomatic period provides an opportunity for presymptomatic diagnosis and therapeutic intervention, ideally the administration of neuroprotective compounds. Although the concept of a threshold for onset of symptoms is widely accepted, it has only been determined experimentally very recently, in nonhuman primates (Bezard et al., 2001) chronically treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) according to a regimen that produces a progressive Parkinsonian state (Bezard et al., 1997b). Among different parameters, the level of DA transporter (DAT), which is localised on presynaptic nerve terminals of nigrostriatal neurons, has been measured by binding of specific ligands to characterise the DA nerve terminal density in striatum (Bezard et al., 2001). The DAT was labeled with iodinated cocaine tropane derivative PE2I (N-(3-ioprop-2E-enyl)-2-␤-(4-methylphenyl)nortropane). PE2I has very high affinity and selectivity for DAT sites (Emond et al., 1997; Chalon et al., 1999) and has extremely low affinity for serotonin and noradrenaline transporters compared to ␤CIT (Guilloteau et al., 1998). It is interesting that PE2I can be used in vitro when labelled with 125I, in vivo for single photon emission computerized tomography (SPECT) when labelled with 123I, and for positron emission tomography when labelled with 11C (Halldin et al., 2001). Thus, in order to assess PE2I SPECT imaging for presymptomatic diagnosis of PD, we used this progressive chronic MPTP lesioned nonhuman primate model in order to follow the progression of striatal dopaminergic lesions with 123I-PE2I SPECT applying Logan’s graphical method for quantification (Logan et al., 1990, 1996).

Materials and methods Animals Experiments were conducted using four female cynomolgus monkeys (Macaca fascicularis, CRP, Port Louis, Mauritius, mean age ⫽ 3.1 ⫾ 0.3 years; mean weight ⫽ 3.0 ⫾ 0.2 kg). Animals were housed in individual primate cages under controlled conditions of humidity (50 ⫾ 5%), temperature (24 ⫾ 1°C), and light (12 h light/12 h dark); food and water were available ad libitum and their care was supervised by veterinarians skilled in the healthcare and maintenance of nonhuman primates. Experiments were performed in accordance with European Communities Council Directive of 24 November 1986 (86/609/EEC) for care of laboratory animals. All efforts were made to minimise animal suffering and to use the minimum number of animals. To maximise data obtained from these animals, brain tissue

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acquired in the present experiment will be used for further experiments on PD pathophysiology. Experimental protocol Two of the four animals were treated daily (8:00 AM) with injections of MPTP hydrochloride (0.2 mg/kg, iv; Sigma, St. Louis, MO) in saline according to a previously described protocol (Bezard et al., 1997a, 1997b, 1999). Animal behaviour was assessed daily (11:00 AM) on a Parkinsonian monkey rating scale, using videotape recordings of monkeys in their cages and clinical neurological evaluation as previously described (Bezard et al., 1997a; Imbert et al., 2000). During each session, two examiners evaluated the animals’ level of motor performance, coaxing them to perform various tasks by offering appetising fruits. The minimal disability score was 0 and the maximum score was 25 (Imbert et al., 2000). Differences in rating were discussed regularly to eliminate observer idiosyncrasy (Taylor et al., 1994). MPTP administration was terminated when they reached a score over 8 on the behavioural rating scale. Clinical symptoms continued to develop for several days after the treatment was stopped, due to the long-term action of MPP⫹ (Jackson-Lewis et al., 1995). SPECT imaging was performed at Day 0 (D0, n ⫽ 4), D6 (n ⫽ 2), D12 (n ⫽ 2), D15 (n ⫽ 2), and D20 (n ⫽ 2) of the experimental protocol of intoxication at 12:00 (noon). Then all animals were killed by sodium pentobarbital overdose (150 mg/kg, iv) and the brains were quickly removed and frozen after death for further postmortem analysis. Preparation of

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I-PE2I and metabolite analysis

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I-PE2I was prepared by iododestannylation of the tributyltin precursor (74 MBq [123I]Nal, specific activity ⬎ 185 TBq/mmol; Schering-CIS-BioInternational, France) according to a previously described method. The radioiodinated solution was purified by HPLC using a reverse-phase column C18 and a mixture of MeOH/H2O/Et3N (75/25/0.2) as mobile phase. At the end, eluted 123I-PE2I was mixed with 1 ml sterile 0.9% NaCl for iv injection. SPECT acquisition and reconstruction Anaesthesia was induced by ketamine (im, 15 mg/kg, Imalgene, Centavet, France) and maintained with passive inhalation of oxygen/isoflurane at 2.1 l/min (12:30 AM). A polycarbonated custom-made device maintained the monkey’s head in the SPECT camera to allow reproducible positioning of the animal, whose body temperature was regulated using a heating pad (Jide´ Medical, Limoges, France). The brain camera (Ceraspect DSI, Boston, MA) was calibrated in kBq/ml by using a plexiglass ghost (coefficient ⫽ 0.246667). Acquisitions began immediately after a bolus injection of 123I-PE2I (84 ⫾ 8.4 MBq) in the

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femoral vein every 3.57 min in a sequential manner over 120 min. Cross-sections were reconstructed by back projection with a 2D Hanning filter (order ⫽ 0.5). SPECT data were reoriented according to a line passing through the inferior part of frontal and occipital lobes. The five slices corresponding to the highest striatal uptake were digitally summed, yielding a final transverse slice 10 mm thick. No attenuation correction was applied. Kinetic analysis of analysis

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I-PE2I and imaging protocol

Reproducibility of the tomographic technique was ensured by repeating the assessment twice in the four normal animals. The D0 values are the mean of these two sessions. In normal animals, standardised oval regions of interest (ROI) for right and left striata and for occipital cortex were defined on a chosen transverse slice. These geometrical ROIs had a volume of 0.35 ml for striatum according to macaque brain anatomical data (Franc¸ois et al., 1996). Localisation of striatal ROI on transverse slices was determined according to a median sagittal line and a perpendicular line passing through the temporal lobes. The mean activity in the D0-determined striatal and occipital ROIs [respectively, S(T) and O(T)] were counted at each SPECT acquisition after 123I-PE2I injection in normal and MPTPlesioned monkeys. Indeed, the ROIs determined at D0 were then used in the course of MPTP intoxication to take advantage of the experimental design that allows repeated measures in the same animal. In MPTP-treated animals we used the same size of ROIs without considering potential striatal atrophy consecutive to MPTP intoxication. The graphical Logan’s method was used to determine the distribution volume ratio (DVR) between the striatal and occipital regions (Logan, 2000). Integrated striatal activity from zero to T, normalised to striatal activity at time T, was plotted vs integrated occipital activity from zero to T normalised to striatal activity at time T. According to Logan’s model the plot becomes linear when the ratio between occipital and striatal activity becomes constant. The asymptotic slope equals DVR: [integral(0,T)S(t)dt]/S(T) vs [integral(0,T)O(t)dt]/S(T). DVR is related to the binding potential (BP) by: DVR ⫽ 1 ⫹ BP. Binding potential is assimilated to density of transporters. Analysis was performed using the Kaleidagraph program (Kaleidagraph 3.5, Synergy Software, Reading, PA). The mean value of BP at D0 (calculated from two independant experiments in each of the four monkeys) was considered as 100%. The results at D6 (n ⫽ 2), D12 (n ⫽ 2), D15 (n ⫽ 2), and D20 (n ⫽ 2) were then expressed as the mean percentage of decreased DAT density (BP). DVR was equal to 1 when the volumes of distribution were the same between striatum and occipital lobe, when no specific binding on DAT existed.

Results Kinetics of

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I-PE2I in normal monkeys

In the four normal monkeys SPECT images showed high concentrations of PE2I in striatum, minimal accumulation in thalamus and midbrain, and minimal nonspecific uptake in cortex (Fig. 1, D0). Time-activity curves of PE2I for the striatum and occipital cortex showed very rapid kinetics (Fig. 2). After a bolus injection in the femoral vein, striatal accumulation of the tracer was very rapid, reached a maximum at 15–20 min, then slowly decreased. This aspect is compatible with reversible binding of PE2I to DAT. In occipital cortex, where DAT is almost absent (Ciliax et al., 1999), nonspecific uptake reached a maximum earlier than in the striatum at 5–10 min postinjection and then decreased very rapidly. Using Logan’s graphical method, linearisation of the plots [integral(0,T)S(t)dt]/S(T) vs [integral(0,T)O(t)dt]/S(T) was observed after the fifth or sixth acquisition 16 –19 min after injection in each of the four monkeys (Fig. 3). The mean correlation coefficient of the slope was 0.993 ⫾ 0.003 in all monkeys. Mean DVR was of 3.1 (2.85–3.3) for monkey 1, 1.8 (1.7 and 1.6 –1.95 and 2.0) for monkeys 2 and 4, and 2.9 (2.65–3.1) for monkey 3 (Table 1). Thus BPs were 2.1 for monkey 1, 0.8 for monkeys 2 and 4, and 1.9 for monkey 3. MPTP-induced changes in motor behaviour As previously reported with this administration protocol (Bezard et al., 1997b, 2001), monkeys at D6 did not exhibit Parkinsonian motor symptoms (Parkinsonian score of 0 for both animals). Animals at D6 were thus considered as asymptomatic. Monkeys assessed at D12, D15, and D20 exhibited Parkinsonian motor abnormalities (Table 1). The transition between the presymptomatic and symptomatic periods thus occurred between D6 and D12 of the intoxication protocol. Kinetics of

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I-PE2I in MPTP-treated monkeys

Visual analysis of SPECT images failed to distinguish a decrease in 123I-PE2I uptake at D6, while it concluded decreased uptake at D12 and D15 and no specific uptake of the tracer at D20 (Fig. 1). The kinetics of PE2I is more rapid in MPTP-lesioned monkeys than in normal monkeys. At D12 and D15, the peak of time-activity curves was reached at 10 –15 min, while return to background activity was also more rapid (Fig. 2). At D20 and D25, the time-activity curve of striatum followed the same shape as the occipital cortex. Linearisation of Logan’s plots [integral(0,T)S(t)dt]/S(T) vs [integral(0,T)O(t)dt]/S(T) has always been obtainable, although, interestingly, slopes decreased progressively during MPTP intoxication (Fig. 3). Binding potential decreases were 42, 79, and 89% for monkey 3 and 44, 50, and 87% for

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Fig. 1. SPECT images (Ceraspect, DSI, second Hanning filter) of transverse slices of the striatum at Days 0, 6, 12, and 15 of animal M3. The oval regions of interest on striatum and occipital lobe allowed quantification with Logan’s graphical method. We quantified the volume of distribution (DVR) that decreased from Day 6 onwards.

monkey 4 at D6, D12, and D15, respectively. The mean BP decrease was then 43% at D6, 64% at D12, and 88% at D15. At D20 for the two monkeys, DVR were equal to 1 (BP ⫽

0) since no specific uptake was detected, thus corresponding to a nearly complete lesion.

Discussion

Fig. 2. The left side of the figure shows the kinetics of 123I-PE2I in animal M3 at D0 and D12 of MPTP intoxication in striatum and occipital lobe. The right side shows quantification of the distribution volume ratio (DVR) of 123 I-PE2I according to Logan’s graphical method and slope of Logan’s plot.

The present study, utilising an MPTP-lesioned nonhuman primate model designed to mimic the progression of PD, demonstrates that presymptomatic diagnosis of PD is feasible using 123I-PE2I SPECT. Comparison between the present study and a previous in vitro 125I-PE2I autoradiographic study in animals intoxicated according to the same regimen supports our interpretation (Bezard et al., 2001). While such a presymptomatic diagnosis was considered only possible using expensive fluorodopa positron emission tomography (Morrish et al., 1998), our results suggest that simple and widely available SPECT cameras could be used for presymptomatic diagnosis of PD and accurate follow-up of disease progression. Unlike other DAT ligands, PE2I is highly specific of the DAT since it accumulates mainly in striatum in very high concentrations, and does not accumulate in regions rich in the serotonin or noradrenaline transporter (thalamus, hypothalamus, and midbrain) (Guilloteau et al., 1998; Chalon et al., 1999). Due to its affinity for the DAT, and since the MPP⫹, the active metabolite of MPTP, is uptaken by the same DAT, a competition cannot be excluded. PE2I, a nortropane analog, would block the uptake resulting even-

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Fig. 3. Logan’s plot of 123I-PE2I in animal M3 at D6, D12, and D15. Slope of Logan’s plot determined the distribution volume (DVR) of decreased progressively in relation to the duration of chronic MPTP intoxication (see Table 1 for values).

tually in a decreased neurotoxicity of MPP⫹ (Jaber et al., 1997). However, the kinetics of degeneration we report here is comparable to the progression determined from postmortem measurements. This suggests that underestimation of DAT binding at D6 and D12, the only time points where MPP⫹ is present, is unlikely. Time-activity curves confirmed that the PE2I tracer exhibits reversible binding on DAT, since its kinetics are very rapid, as shown for example by the 123I-IACFT (Altropane) (Bonab et al., 2000). Such reversible binding and rapid kinetics make possible the use of the graphical method developed by Logan (Logan et al., 1990). A recent study has shown that accurate quantification of PE2I binding to DAT can be achieved with Logan’s graphical method without blood sampling (Pinborg et al., 2002). At transient equilibrium, i.e., 15–20 min postinjection in normal (i.e., nonle-

Table 1 Clinical scores and distribution volume ratios (DVR) of D0

M1 M2 M3 M4

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DVR

0 0 0 0

3.1 1.8 2.9 1.8

I-PE2I and

sioned) monkeys, the Logan plot became linear. According to Logan’s graphical method, linearisation allows quantification of DVR of PE2I. Apparent density in DAT is then deduced from DVR (BP ⫽ DVR ⫺ 1, BP ⫽ Bmax/Kd) (Logan, 2000). DVR measured in normal monkeys showed inter- but not significant intraindividual variability. The interindividual variability is thus greater than that of in vitro autoradiographic studies using 125I-PE2I in the same species (Bezard et al., 2001). This interindividual variability may partly include a partial volume effect on deep and small brain structures that induce variations in intensity and the limit of geometric ROIs. Drawing of ROIs may be greatly improved by anatomical boundaries with fusion of SPECT with MRI, and multimodality will permit correction of partial volume effect. These limits emphasise the need to perform repeated measures, i.e., to use the same monkey as its

I-PE2I in normal (n ⫽ 4) and chronically MPTP-treated animals (n ⫽ 2)

D6

Clinical score

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D12

D15

D20

Clinical score

DVR

Clinical score

DVR

Clinical score

DVR

Clinical score

DVR

0 0

2.1 1.45

10 7

1.4 1.4

19 20

1.2 1.1

25 25

1 1

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own control for successive SPECT sessions. In humans, intersubject variability with PE2I has to be explored but does not seem negligible (Poyot et al., 2001). If this variability is proved, it will stress the necessity of repeated SPECT acquisitions in the same patient to demonstrate progressive neuronal degeneration or neuroprotective effect of drugs. In the course of MPTP treatment, the plots [integral(0,T)S(t)dt]/S(T) vs [integral(0,T)O(t)dt]/S(T) demonstrated a progressive decrease of slopes of “Logan plots.” At D6, the visual analysis of SPECT images and the kinetics curve were similar to that at D0, i.e., in normal monkeys, whereas mean BP decreased by 43%. The previous autoradiographic study also indicated a significant decrease at D6 (⬃30%), thus validating the Logan approach. From the time the animals displayed Parkinsonian motor abnormalities, i.e., D12, a decrease can be detected by visual analysis as further confirmed by modification of kinetics curves in striatum. Accordingly, the Logan plot slope significantly decreased (Fig. 3). DVR decrease at D12 and D15 (Table 1) is comparable to the diminution in DAT binding measured autoradiographically in vitro (Bezard et al., 2001). After D20, i.e., in animals exhibiting a full repertoire of PD symptoms, 123I-PE2I kinetics in striatum were roughly similar to those in occipital cortex, as reported both in our previous in vitro study (⫺97.3%; Bezard et al., 2001) and in a PET study with 11C-PE2I, comparing only normal and Parkinsonian baboon (Poyot et al., 2001). Postmortem 125IPE2I binding showed near total decrease in DAT in the present study (data not shown). The quantification of DVR by the method of Logan (Logan et al., 1996) is the only one able to show a significant decrease in uptake, as soon as the sixth day of MPTP intoxication when qualitative visual analysis does not detect any change. Such an early measurement of partial striatal dopaminergic denervation is made possible by the high specificity of PE2I; however, the small size of macaque brain does not allow accurate discrimination of the striatal subregions when using SPECT imaging. For the first time, it has been possible to follow in vivo nigrostriatal degeneration and to validate the technique in parallel with an in vitro study (Bezard et al., 2001). Improvement must be made, especially regarding the determination of the DVR in a large number of healthy people, before proposing the use of PE2I SPECT imaging as an early diagnosis tool. Nevertheless, this preliminary demonstration provides significant insights that support the use of such in vivo investigation in our chronic MPTP-lesioned nonhuman primate model for the study of neuroprotective compounds that would delay the appearance of Parkinsonian symptoms.

Conclusion This study demonstrated that Logan’s graphical method allows the quantification of 123I-PE2I binding potential.

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I-PE2I SPECT determined quantitative assessment of presynaptic dopaminergic nigrostriatal neuron loss specifically induced by MPTP in nonhuman primates. We have shown in this feasibility study that PE2I SPECT indicates neuronal degeneration before clinical behavioral changes. SPECT could then determine preclinical Parkinson’s disease. The future therapeutic approaches of PD will be neuroprotection. In vivo dopaminergic tracers such as PE2I will be very useful to diagnose Parkinson’s disease in the early stages and to follow effects of new therapies.

Acknowledgments E.B. was the recipient of a grant from the Socie´te´ de Secours des Amis des Sciences. The University of Tours, the INSERM, the University of Bordeaux, and the CNRS funded this study. We wish to thank Dr. P. Ravenscroft for critical reading.

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