During in vivo intracerebral infusions, the ability to perform accurate targeting towards a 3D-specific point allows control of the anatomical variable and identification of the effects of variations in other factors. Intraoperative MRI navigation systems are currently being used in the clinic, yet their use in nonhuman primates and MRI monitoring of intracerebral infusions has not been reported. In this study rhesus monkeys were placed in a MRI-compatible stereotaxic frame. T1 MRIs in the three planes were obtained in a 3.0T GE scanner to identify the target and plan the trajectory to ventral postcommisural putamen. A craniotomy was performed under sterile surgical conditions at the trajectory entry point. A modified MRI-compatible trajectory guide base (Medtronic Inc.) was secured above the cranial opening and the alignment stem applied. Scans were taken to define the position of the alignment stem. When the projection of the catheter in the three planes matched the desired trajectory to the target, the base was locked in position. A catheter replaced the alignment stem and was slowly introduced to the final target structure. Additional scans were performed to confirm trajectory and during the infusion of a solution of gadoteridol (ProHance, Bracco Diagnostics; 2 mM/L) and bromophenol blue (0.16 mg/ml) in saline. Monitoring of the pressure in the infusion lines was performed using pressure monitoring and infusion pump controller system (Engineering Resources Group Inc.) in combination with a MRI-compatible infusion pump (Harvard). MRI during infusion confirmed successful targeting and matched postmortem visualization of bromophenol blue. Assessment of the accuracy of the targeting revealed an overall 3D mean ± SD distance error of 1.2 ± 0.6 mm and angular distance error of 0.9 ± 0.5 mm. Our results in nonhuman primates confirm the accuracy of intraoperative MRI intracerebral navigation combined with an adaptable, pivot point-based targeting system and validates its use for preclinical intracerebral procedures.

This study assessed the potential for functional and anatomical recovery of the diseased aged primate nigrostriatal system, in response to trophic factor gene transfer. Aged rhesus monkeys received a single intracarotid infusion of MPTP, followed one week later by MRI-guided stereotaxic intrastriatal and intranigral injections of lentiviral vectors encoding for glial derived neurotrophic factor (lenti-GDNF) or beta-galactosidase (lenti-LacZ). Functional analysis revealed that the lenti-GDNF, but not lenti-LacZ treated monkeys displayed behavioral improvements that were associated with increased fluorodopa uptake in the striatum ipsilateral to lenti-GDNF treatment. GDNF ELISA of striatal brain samples confirmed increased GDNF expression in lenti-GDNF treated aged animals that correlated with functional improvements and preserved nigrostriatal dopaminergic markers. Our results indicate that the aged primate brain challenged by MPTP administration has the potential to respond to trophic factor delivery and that the degree of neuroprotection depends on GDNF levels.

Parkinson's disease (PD) researchers have pioneered the use of cell-based therapies (CBTs) in the central nervous system. CBTs for PD were originally envisioned as a way to replace the dopaminergic nigral neurons lost with the disease. Several sources of catecholaminergic cells, including autografts of adrenal medulla and allografts or xenografts of mesencephalic fetal tissue, were successfully assessed in animal models, but their clinical translation has yielded poor results and much controversy. Recent breakthroughs on cell biology are helping to develop novel cell lines that could be used for regenerative medicine. Their future successful clinical application depends on identifying and solving the problems encountered in previous CBTs trials. In this review, we critically analyze past CBTs' clinical translation, the impact of the host in graft survival, and the role of preclinical studies and emerging new cell lines. We propose that the prediction of clinical results from preclinical studies requires experimental designs that allow blind data acquisition and statistical analysis, assessment of the therapy in models that parallel clinical conditions, looking for sources of complications or side effects, and limiting optimism bias when reporting outcomes.