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. Author manuscript; available in PMC: 2008 Dec 19.
Published in final edited form as: Cell Transplant. 2008;17(4):417–425.

Pharmacological MRI (phMRI) Monitoring of Treatment in Hemiparkinsonian Rhesus Monkeys

Liming Luan *,†,1, Feng Ding *,†,1, Yi Ai *,‡, Anders Andersen ‡,§, Peter Hardy §, Eric Forman *, Greg A Gerhardt *,‡, Don M Gash *,‡, Richard Grondin *,‡, Zhiming Zhang *,‡,§
PMCID: PMC2605704  NIHMSID: NIHMS83174  PMID: 18522244

Abstract

There is a great need for the development of noninvasive, highly sensitive, and widely available imaging methods that can potentially be used to longitudinally monitor treatment of Parkinson’s disease (PD). Here we report the monitoring of GDNF-induced functional changes of the basal ganglia in hemiparkinsonian monkeys via pharmacological MRI measuring the blood oxygenation level-dependent (BOLD) response to a direct dopamine agonist (apomorphine, APO). After testing BOLD responsiveness to APO in their normal state, two additional scans were taken with the same dose of APO stimulation after induced parkinsonism. Then all animals were chronically treated with GDNF for 18 weeks by a programmable pump and catheter system. The catheter was surgically implanted into the right putamen and connected to the pump via flexible polyurethane tubing. phMRI scans were taken at both 6 and 18 weeks while they received 22.5 μg of GDNF per day. In addition, behavioral changes were monitored throughout the entire study. The primary finding of this study was that APO-evoked activations in the DA denervated putamen were attenuated by the chronic intraputamenal infusion of GDNF accompanied by improvements of parkinsonian features, movement speed, and APO-induced rotation compared to data collected before the chronic GDNF treatment. The results suggest that phMRI methods in combination with administration of a selective DA agonist may be useful for monitoring neurorestorative therapies in PD patients in the future.

Keywords: Apomorphine, GDNF, phMRI, Rhesus monkey, Parkinson’s disease, MPTP, Pump, Catheter, Putamen

INTRODUCTION

Dopamine (DA) plays a pivotal role in Parkinson’s disease (PD). This has resulted in attempts to visualize its changes in the living brains of PD patients by using various neuroimaging techniques such as positron emission tomography (PET) with [18F]fluorodopa to measure striatal DA levels and photon emission computed tomography (SPECT) with [123I]IBZM to study DA receptors [for reviews, see (11,12,27)]. The development of pharmacological MRI (phMRI) has allowed investigators to visualize DA systems in a living brain without the injection of radioactive tracers. phMRI is based on changes of the blood oxygen level-dependent (BOLD) signal upon a CNS drug challenge (21,31). The nonselective DA receptor agonist apomorphine (APO) was used to stimulate postsynaptic DA receptors in this study. phMRI has shown the capacity of mapping the nigrostriatal DA system in the nonhuman primate model of PD (8,39). For example, Zhang and colleagues (39) reported for the first time a positive correlation between the BOLD response to d-amphetamine (which evokes DA release) and dopaminergic neurons in the substantia nigra pars compacta (SNc) ipsilateral to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administration.

Glial cell line-derived neurotrophic factor (GDNF) protects and restores the nigrostriatal dopaminergic system in rodent and nonhuman primate models of PD (4, 15,18,23,30). This trophic factor has also shown promise in phase I clinical trials for the treatment of PD (17,29). Ample evidence has proven that GDNF can protect and promote survival of presynaptic dopaminergic neurons in the SNc and axons in the striatum (15,36).

This pilot study was designed to test the hypothesis that phMRI techniques combined with the use of selective dopaminergic agonists can be employed to monitor treatment of PD. Specifically, this study was designed to determine if the amplitude of APO-induced activations in the MPTP-lesioned putamen can be attenuated by chronic GDNF treatment in parkinsonian rhesus monkeys. We have previously reported that the majority of APO-induced activations were observed in the MPTP-lesioned striatum due to DA deficiency, which results in increases of sensitivity levels of postsynaptic DA receptors toward challenges of a DA agonist like APO in nonhuman primates (37). Because APO can directly stimulate supersensitive postsynaptic DA receptors in the denervated striatum (28) and has been used in the clinic for treatment of PD, we believe that the pharmacological actions of APO can provide information on postsynaptic changes in dopaminergic pathways of the nigrostriatal system. Those changes should be detectable by phMRI methods based on previous studies (35,38,39).

MATERIALS AND METHODS

Animals

Three adult female rhesus monkeys (Macaca mulatta) were obtained from a commercial supplier (Covance, Alice, TX) and were housed in individual cages in a temperature-controlled room and maintained on a 12-h light and 12-h dark cycle. Water was available ad libitum. Standard primate biscuits were supplemented daily with fresh fruits and vegetables. The animals’ care was supervised by experienced veterinarians and all protocols used in the study were approved by the University of Kentucky’s Animal Care and Use Committee.

As reported in detail elsewhere (2,38,39), the animals were trained for phMRI scans under full conscious alert conditions prior to MPTP administration. Briefly, the animals were adapted to an MRI-compatible chair constructed from nonferromagnetic materials and designed to comfortably position an adult rhesus monkey within the magnet bore in a prone position. Under local anesthesia (1% lidocaine, 1.0 ml on each side), two MRI-compatible pins were inserted through the overlying skin and connective tissue to contact the bony cranium. In addition, earbars, constructed to follow the natural angle of the rhesus ear canal (10–15° down from horizontal), were fashioned from nylon and secured to the chair’s head holder. Inserted into the animal’s ears, the ear bars provided additional restraint to head motion. The ear bars also functioned to reduce the gradient noise during phMRI scanning. During training sessions, animals were allowed to watch movies and each session lasted 45–75 min. The entire chair training usually took 2 months.

MPTP Administration and Behavioral Assessments

After baseline data collection, including behavior and phMRI, the animals received right intracarotid artery infusions of 2.4 mg MPTP per animal (i.e., 0.4 mg/kg for a 6-kg animal) to induce continuously expressed unilateral parkinsonian features contralateral to the affected brain (3,26). Behavioral tests were not conducted until full and stable PD features had developed. Typically, this took 2–3 months. The evaluation of parkinsonism was based on weekly videotaped behavior in the animal’s home cage including bradykinesia, rigidity, posture, balance, and APO-induced rotational behavior. The videotapes were evaluated by two well-trained and experienced raters. The interclass correlation of independent measurements of parkinsonian features was r = 0.81. In addition to the clinical rating scale, movement speed was also quantified by using the automated video-tracking system, EthoVision® (34).

Procedures for phMRI Scans

The phMRI scans were conducted on a Siemens VISION 1.5 T MRI scanner using the body coil to transmit radio frequency and an 8-cm-diameter surface coil placed above the monkey’s head for RF signal reception. The anatomical structures of interest were visualized using a 3D FLASH sequence with 1-mm isotropic resolution (TR/TE = 21/6 ms, flip angle = 30°, image matrix size = 128 × 128 × 90, field of view = 128 mm). The functional MR images from pharmacological challenges were acquired continuously using a FLASH 2D multiple gradient-recalled-echo (MGRE) navigator sequence (39). Slices were acquired interleaved for two noncontiguous coronal sections: the first slice covering the area of the rostral putamen and caudate nucleus, and the second covering the substantia nigra (Fig. 1). An 11-echo MGRE sequence was used to map, on a pixel-by-pixel basis, the local transverse relaxation rate R2*, an intrinsic MRI parameter sensitive to changes in local cerebral blood flow and oxygenation associated with changes in cerebral activity (7,8,37-39). The last TE images were acquired without phase encoding gradients to serve as a navigator echo for detection of head motion during the acquisition of data for a single calculated R2* image. The FLASH 2D acquisition parameters were: TR = 250 ms, TE = 7–75 ms, ΔTE = 6.5 ms, image matrix size = 112 × 128, field of view = 128 mm, slice thickness = 3 mm, flip angle = 40°, bandwidth = 156 Hz/pixel. The changes in response to dopaminergic stimulations were averaged spatially across pixels within individual ROIs selected in the caudate nucleus, putamen, GPi, GPe, and substantia nigra (Fig. 1). The ROI dimensions were 3 × 3 × 3 mm, each representing a 27 mm3 volume. ROIs were manually selected in both hemispheres of MPTP-lesioned and normal control animals based on the co-registered 3D anatomical images acquired from the FLASH sequence. Because of variability in the inherent noise level due to differences in positioning animals for each scan and the movements during scanning, the replicate scans were treated as independent observations in the analysis. Some partial volume effects are unavoidable, especially in the through-slice direction and for smaller structures such as the substantia nigra. To minimize these effects, we used multiple animals and each animal underwent two replicate scans using the same protocol. Small, unavoidable differences in slice placement between the two scans helped to ensure that no systematic errors were committed in the ROI selection. Prior to the administration of apomorphine, a total of 40 image frames were collected over 20 min to determine the baseline state. Following injection of APO, an additional 40 frames were collected to track the dynamic response (2,38,39). The change in R2* (i.e., ΔR2*), which represents the phMRI activation response to drug, was determined as the difference between the mean R2* across 20 images postdrug administration during the period of peak response (5–15 min) and the mean R2* within the 40 baseline images. A reduction (“negative” change) in R2* associated with a local decrease of paramagnetic deoxyhemoglobin is an indicator of a BOLD effect activation (7,39).

Figure 1.

Figure 1

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Region of interest for apomorphine-evoked activation. Shown are the two coronal slices through the basal ganglia. Three ROIs on each side were analyzed including the caudate nucleus (1), putamen (2), substantia nigra (3). Scale bar: 5 mm.

Catheter/Pump Implantation

Following the baseline imaging in the parkinsonian state, the animals had a multiport catheter implanted in the right putamen using MRI-guided stereotactic procedures. The catheter was connected via flexible polyurethane tubing to a programmable pump (SynchroMed™ model 8616-10; Medtronic, Minneapolis, MN), which was placed in a pocket of a jacket worn by the monkey. Placement of the catheter was verified by anatomical magnetic resonance imaging, 48–72 h postsurgery (Fig. 2). The detailed description for these procedures has been published elsewhere (1,18,19). On weeks 6 and 18 posttreatment, phMRI studies were conducted on all animals while receiving 22.5 μg/day GDNF (1,18).

Figure 2.

Figure 2

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Catheter track in right central putamen. The catheter tract is indicated by arrows on the T1-weighted image. 1, caudate nucleus; 2, putamen. Scale bar: 5 mm.

Immunohistochemical Staining for GDNF

At the conclusion of GDNF intraputamental infusion, the animals were euthanatized by an overdose of pentobarbital followed by transcardial perfusion of 6 L ice-cold saline. The brains were removed, placed in an ice-cold brain mold, and sliced into 4-mm-thick coronal slabs, which were then immersion fixed in 4% paraformaldehyde at 4°C. The sections with the striatum were then cut at 40 μm thick and stained immunohitochemically for GDNF (polyclonal antibody, 1:1500; Chemicon International) to examine the diffusion from the catheter.

Statistical Analyses

The behavioral response to APO administration, including changes in parkinsonian ratings and movement speed, was analyzed by two-tailed paired t-tests. For the evaluation of phMRI data, two-sided independent sample t-tests were used to evaluate drug effects in the separate ROIs. The calculation of total mean-squared error includes contributions from within-animal residual variation in the phMRI time-series response data along with variability across replicate scans and between animals. The analysis is described in more detail elsewhere (2,38, 39). In all tests, a value of p < 0.05 was considered significant.

RESULTS

All animals expressed stable, unilateral parkinsonian features from the eighth week post-MPTP administration, including bradykinesia, rigidity of the left upper and lower limbs, stooped posture, and balance instabilities. These parkinsonian features were significantly improved except for posture by 0.1 mg/kg APO treatment (Fig. 3, filled columns). Additionally, APO-induced counterclockwise rotational behavior (turning toward MPTP lesioned side) was observed in all animals.

Figure 3.

Figure 3

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Apomorphine significantly improved parkinsonian features including bradykinesia, rigidity on upper and lower limbs, and balance as evaluated using a nonhuman primate parkinsonian rating scale. UL: upper limb; LL: lower limb. *p < 0.05.

No complications were encountered during catheter implantation into the putamen in any of the animals. Also, no adverse effects were observed following the surgery or during chronic GDNF treatment. While a steady improvement was evident post-GDNF delivery, there was an average of 22% improvement in the motor functions as per the nonhuman primate parkinsonian rating scale by the sixth week of the treatment (Fig. 4A), which was maintained up to 18 weeks. The improvements in motor function were also evident from increased movement speed (Fig. 4B). The improvements seemed to parallel the parkinsonian rating scale. Furthermore, GDNF significantly reduced APO-induced rotations (Fig. 4C) by 87% at the sixth week. A similar reduction was also seen at the 18th week posttreatment.

Figure 4.

Figure 4

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Chronic intraputamenal infusion of GDNF improved parkinsonian features (A), movement speed (B), and reduced APO-induced rotations (C) at weeks 6 and 18 posttreatment. *p < 0.05; **p < 0.01.

As previously reported (39), while little changes were found in the putamen and caudate nucleus prior to MPTP treatment (Fig. 5A), strong APO-induced activations were seen in the same regions on the ipsilateral side of MPTP administration (Fig. 5B, Fig. 7A). As predicted, chronic intraputamenal infusion of GDNF not only significantly improved motor function but also reduced the APO-induced activation in the putamen on the ipsilateral side to GDNF infusion at the sixth and 18th week compared to the data collected prior to GDNF treatment. The BOLD activations were significantly reduced at both 6 and 18 weeks after the treatment, falling much closer to the baseline levels in DA denervated putamen (Fig. 6A). However, GDNF-induced functional changes in the caudate nucleus seemed to be biphasic (i.e., APO-induced activation was slightly higher at the sixth week and significantly decreased at the 18th week posttreatment) (Fig. 6B)). There was little change in BOLD signal in the SN (data not shown). Typical changes of BOLD signal in response to GDNF treatment are shown in Figure 7 (monkey #445). The BOLD effect was superimposed on a T1-weighted image from the same monkey collected on the same day. The size of APO-evoked activation was significantly reduced compared with data collected before chronic GDNF treatment.

Figure 5.

Figure 5

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Average ΔR2* for effects of APO in monkeys (A) pre-MPTP and (B) post-MPTP. APO-evoked activation in the MPTP-lesioned and deactivation (inhibitory effect) in the intact side is shown, beginning 2–3 min after drug administration. *p < 0.05 comparing the left with the right side.

Figure 7.

Figure 7

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Coronal view of the sites and strength of activation. BOLD response to APO (A) prior to GDNF and (B) at 18 weeks post-GDNF treatment are shown. The ΔR2* map was overlaid on the T1-weighted 3D anatomic image at the same site.

Figure 6.

Figure 6

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Average ΔR2* for right rostal putamen (A) and right caudate nucleus (B). Intraputamenal GDNF administration decreased APO-evoked activation in the putamen, with the responses measured at 6 and 18 weeks. The responses in the caudate nucleus appeared to be biphasic, with activation increasing at 6 weeks and decreasing to more normal levels by 18 weeks of treatment. *p < 0.05; **p < 0.01.

Postmortem analysis showed the radius of diffusion from the catheter. Positive GDNF staining was observed in most of the treated putamen (Fig. 8). The spread of GDNF along the catheter track was seen in all monkeys with a diffusion radius of at least 3 mm at the tip of the catheter.

Figure 8.

Figure 8

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Immunohistology shows the diffusion of GDNF from the catheter opening in the putamen to cover broad areas of the putamen, internal capsule, and small portion of the caudate nucleus. Some tissue around the catheter track (*) was lost in processing. Acb: nucleus accombens; Cd: caudate nucleus; ic: internal capsule; LV: lateral ventricle; Put: putamen. Scale bar: 1 mm.

DISCUSSION

The primary finding of this study was that APO-evoked activations in the DA denervated putamen were attenuated by the chronic intraputamenal infusion of GDNF accompanied by improvements of parkinsonian features, movement speed, and APO-induced rotation. The results suggest that phMRI methods in combination with administration of a selective DA agonist may be useful for monitoring neurorestorative therapies in PD patients in the future.

The reasons for specifically selecting APO for stimulating the dopaminergic nigrostriatal system for this study were as follows: 1) it has been previously demonstrated that phMRI can specifically detect APO-induced activations in the parkinsonian rhesus brain (39), and 2) APO has been widely used as a DA agonist in animal research for three decades. For example, in unilateral 6-hydroxydopamine-lesioned rats, a standard rodent model of PD, APO challenge has been used as a method to assess the severity of lesions judged by the number of turns toward the lesioned side (33). The rotational behavior could also be improved by GDNF in rats (14,22). Finally, APO is also widely used in the clinic, especially to treat levodopa-induced motor complications [for reviews see (20,25)].

GDNF has been proven to halt or reverse progressive degeneration of the nigrostriatal DA system in models of PD (5,9,15,16,18,23,32). Results from these studies suggest that the most likely mechanism is through the trophic effects of GDNF on midbrain DA neurons. Denervations of nigrostriatal DA levels will lead to an increased sensitivity of DA receptors to the challenge of DA agonists such as APO (33). Grondin and colleagues (18) demonstrated that GDNF could partially restore dopaminergic functions with chronic intraputamenal infusion of GDNF. They found that infusion of GDNF at 15 μg/day, induced >20% bilateral increases in the number of nigral cells and >75% bilateral increases in dopamine metabolites levels in the striatum. In addition, the DA levels increase more than twofold in the periventricular striatal regions (18). Thus, based on the results from this study, we feel that the supersensitivity of DA receptors could be at least partially normalized by the neurorestorative treatment of GDNF, resulting in a reduction of APO-evoked activation in the MPTP-lesioned putamen.

Levodopa has been a “gold standard” for treatment of PD since it was introduced more than 30 years ago because it provides marked symptomatic benefits to virtually all PD patients and improves their daily living (35). Although the drug is extremely effective, few studies have been done to detremine whether therapeutic and potential toxic effects of the drug can be noninvasively and longitudinally monitored by neuroimaging methods in animal models of the disease. Recently, the relationship between the magnitude of APO-induced pharmacological responses and the behavioral response to levodopa treatment were reported in parkinsonian rhesus monkeys (39). In detail, stronger activations were seen in animals that were less responsive to levodopa treatment. More interestingly, the histological analyses revealed that the monkeys with less responsiveness to levodopa treatment had fewer dopaminergic neurons in the SNc (39). These results suggest a link between the phMRI signal and responsiveness to treatment. The ability to reliably monitor, in a noninvasive and longitudinal manner, therapeutic effects would provide valuable information in assessing the progression of PD and the effects of treatment over time. Indeed, results from many imaging studies have demonstrated the possibility of using neuroimaging methods to monitor therapeutic effects in humans (6,17,24). For example, Gill et al. reported that chronic infusion of GDNF in PD patients produced a 28% increase of [18F]dopa uptake around the tip of the infusion catheter after 18 months (17), which suggests that an increase of DA storage occurred after GDNF treatment. The differences between the study conducted by Gill et al. (17) in PD patients and the present study in nonhuman primates with parkinsonism were the changes in the SN. Little changes of BOLD signal were found in the substantia nigra at week 18 in the rhesus monkeys, while Gill et al. (17) showed an increase of 26% of [18F]dopa uptake in the same region in PD patients. A potential explanation for these differences may be the timing of the scan taken or due to the decreased size of the substantia nigra in the monkeys. For example, [18F]dopa PET scans were taken between 12 and 18 months in the human study, while the phMRI scans were taken between 6 and 18 weeks after the GDNF treatment.

Although the results from the present study suggest that phMRI may have several advantages over other methods, there are key disadvantages to this technique, including the susceptibility to motion artifact, which maybe a major issue for PD patients. We believe that there will be many new challenges when this method is adapted to the clinic in the future. During the last decade, the increasing use of PET and SPECT have involved many PD-related clinical trials but much controversy still exists [for reviews see (10,12,13). For example, there appears to be a discrepancy between current imaging protocols and clinical outcomes. In a National Institute of Health sponsored randomized double-blind study on PD patients receiving either fetal tissue transplants or sham surgery, a 40% increase in [18F]dopa uptake in the putamen contrasted with a modest (nonsignificant) 18% improvement in the mean unified Parkinson’s disease rating scale (UPDRS) in one study involving 40 patients. In a second study involving 34 patients, a 20–30% increase of [18F]dopa uptake was seen in the striatum, but clinical changes failed to reach statistical significance [for a review see (6)]. Most recently, a significant increase was found in [18F]dopa uptake in the putamen of PD patients receiving trophic factor therapy, while clinical improvements did not differ significantly from the control group (24). We believe that phMRI methods may face the similar issues in the future.

In this proof-of-concept study, phMRI showed its potential to be used for monitoring treatments in PD by its capability of detecting functional changes before and after the chronic intraputamenal infusion of the neurotrophic factor, GDNF. The changes in phMRI signals were accompanied by improvements in motor functions and APO-induced rotations. The results from this study combined with our previous findings (39) suggest that phMRI methods could possibility be used for early detection of functional changes in the nigrostriatal system and for longitudinally monitoring of treatments for PD in humans.

Acknowledgments

This study was supported by USPHS NIH grants NS39787, AG013494, and NS050242.

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