Pharmacological MRI (phMRI) monitoring of treatment in hemiparkinsonian rhesus monkeys

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 microg 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.

Figure 1

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.

Figure 2

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.

Figure 3

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.

Figure 4

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.

Figure 5

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 6

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.

Figure 7

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 8

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.