Human/nonhuman primate AC–PC ratio—Considerations for translational brain measurements

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Abstract

This comparative magnetic resonance imaging (MRI) analysis evaluated the ratio of AC–PC (anterior commissure to posterior commissure) distance measures in selected groups of humans and nonhuman primates (NHPs). An understanding of the basis of this ratio between primate species may allow more accurate translation of NHP stereotactic targeting measurements to upcoming human trials. MRI datasets of adult humans [n = 21], and juvenile and adult NHPs (Macaca fascicularis [n = 40], and Macaca mulatta [n = 32]), were evaluated in a mid-sagittal plane to obtain the AC–PC distance measure for each examined subject. Two trained evaluators, blinded to each other's results, carried out three separate measurements of the AC–PC length for each subject. Each observer carried out measurements of the entire dataset [n = 93] before repeating the measurements two additional times. Previous dataset measures were not available for review at the time of subsequent measures. Inter- and intra-observer variabilities were not statistically significant. Minimal intraspecies variation was found in the AC–PC measurement of our human and NHP groups. We found significant interspecies differences, however, more between humans and NHPs, and less between the NHP groups. Regression analysis confirms the strong linear relationship of AC–PC distance based primarily on species in our study groups. Human/NHP AC–PC ratios varied between 2.1 and 2.3 based on the compared NHP species groups. We conclude that the scale differences in brain measurements between NHPs and humans described in this study allows improved translation of stereotactic targeting coordinates in future human clinical trials, which may lead to improved efficacy and safety.

Research highlights

▶ MRI measures of AC–PC distances obtained in three primate species. ▶ Measurements found not to vary significantly within species. ▶ Human/NHP AC–PC ratio varied between 2.1 and 2.3. ▶ AC–PC ratio useful estimating human stereotactic coordinates from NHP data. ▶ Translational information for targeting putamen for therapeutic infusions.

Introduction

The most common stereotactic targets for the treatment of Parkinson's disease (PD) with deep brain stimulation (DBS) are the subthalamic nucleus (STN) and the globus pallidus internus (GPi) (Rezai et al., 2008). Most recently, gene therapy has also been used to target the STN for the treatment of PD (Kaplitt et al., 2007). Because the STN has a small volume, and resides in a well-defined anatomical location, modern stereotactic targeting for DBS (or gene therapy) requires high resolution magnetic resonance imaging (MRI) for localization, with or without target confirmation via electrophysiological recording and/or stimulation (Ondo and Bronte-Steward, 2005, Starr et al., 2002, Starr et al., 2009). On the other hand, while larger subcortical structures such as putamen are easily visualized with MRI and even computed tomography (CT) scans, the larger and less distinct the target region, the more difficulty deciding, with visual cues alone, the optimal site for infusion cannula placement for delivery of therapeutics. While functional neurosurgeons have defined the optimal sites for DBS implantation within the STN (Benabid et al., 1994, Limousin et al., 1995, Starr, 2002, Theodosopoulos et al., 2003), no such optimal targets have been clinically defined within the human putamen for therapeutic infusions. With preclinical (Bankiewicz et al., 2006, Grondin et al., 2002, Sanchez-Pernaute et al., 2001) and clinical data (Eberling et al., 2008, Gill et al., 2003, Lang et al., 2006, Slevin et al., 2007) suggesting that delivery of therapeutics within putamenal foci can be effective in the treatment of PD, defining these optimal target sites in humans begins to gain priority.

A recent preclinical study (Yin et al., 2011) utilizing gene therapy, delivered via real-time convective delivery (RCD) (Fiandaca et al., 2009) to the putamen of parkinsonian nonhuman primates (NHP), has suggested that there may be an optimal site for convection-enhanced delivery (CED) (Bankiewicz et al., 2000, Bobo et al., 1994) within this large subcortical structure. Reproducibly targeting such a locus allows CED to provide the largest volume of distribution (Vd) of the therapeutic agent within the putamen, while minimizing leakage into surrounding structures (Yin et al., 2011). Since there is currently no known anatomical or electrophysiological correlate to this optimal putamenal CED infusion locus, site confirmation strategies used for STN DBS, such as high resolution MRI, and neural recording/stimulation strategies, do not appear helpful for targeting putamenal infusions. Successful putamenal targeting, therefore, requires an understanding of the optimal target volume and demands a delivery modality that features precision and reproducibility. While high-resolution MRI will certainly allow excellent visualization of the human putamen and other subcortical brain structures, the best site for placement of a CED cannula within the human putamen requires translation of stereotactic targeting information from recent NHP studies (Yin et al., 2010, Yin et al., 2011), and an improved understanding of the scale differences between the human and NHP brains.

We have recently described the volumetric differences in striatal brain structures that exist between humans and NHPs (Yin et al., 2009). In this article we investigate a novel method for comparing linear distance measurements within the brains of humans and NHPs using MRI. MRI-based brain atlases, utilizing data from multiple subjects, are now more commonly available for humans (Daniluk et al., 2010, Hasan et al., 2010) and NHPs (McLaren et al., 2009, Vincent et al., 2007). The scope of our analysis is not meant to be an exhaustive definition and comparison of linear distances within the brains of humans and NHPs, and does not pretend to comprehensively analyze all possible variables affecting these measurements. We do present a strategy, based on our available data, for developing a distance measurement ratio (human/NHP), which may be useful in translating preclinical stereotactic measurements for use in future human clinical trials targeting putamen for the treatment of PD. For this purpose, we elected to measure a well-known brain distance, the AC–PC (anterior commissure to posterior commissure) line, which is easily determined on mid-sagittal MRI, and is commonly utilized by functional neurosurgeons and incorporated in the planning algorithms of the majority of commercially available image-guided stereotactic systems. The human/NHP AC–PC ratio allows us to quickly translate NHP stereotactic coordinates into comparable estimates in the human.

Section snippets

Human subjects

Measurement data from normal human and PD individuals was derived from MRIs conducted as part of a prospective, open-label Phase I clinical trial examining the safety and tolerability of putamenal gene transfer in patients with PD at the University of California San Francisco (UCSF). The study was reviewed and approved by the Recombinant DNA Advisory Committee of the National Institutes of Health, the United States Food and Drug Administration, and the Institutional Review Board of UCSF. All

Results

The frequency distribution data for our species groups is presented in Fig. 3, showing human, Cynomolgus, and Rhesus data respectively. Age data was missing on one of our human subjects, so only 20 ages were available for this plot. A relatively normal distribution is presented around a mean age of 69 or 70, except for the outlier (age 88). The ages of the 38 Cynomolgus monkeys (2 animal ages were not available) also appear normally distributed. Our 32 Rhesus monkeys, however, were distributed

Discussion

Translating stereotactic targeting information from NHP studies into humans is not always straightforward. In the treatment of PD with gene therapy (Fiandaca and Bankiewicz, 2010) two major sites of vector delivery have been effectively utilized, the STN and putamen. The results of target transduction in these clinical trials have so far been most effective when covering a small, discrete structure, such as the STN (Kaplitt et al., 2007), that is easily seen on MRI and can be confirmed with

Conclusions

The human/NHP AC–PC ratio is approximately 2. The definition of the scale difference between AC–PC measures of these human and NHP species improves the accuracy of translation of preclinical stereotactic targeting data in planning human clinical trials that require precise stereotactic guidance to subcortical loci within relatively large structures such as the putamen.

Acknowledgements

This work was supported in part by a NIH-NINDS award (U54NS045309), NIH award (P01 CA118816), and a gift from the Kinetics Foundation. We appreciated the statistical assistance of Fred Derrick, Ph.D., Professor of Economics at Loyola University of Maryland's Sellinger School of Business and Management. We are grateful for the technical assistance of John Bringas, Philip Pivirotto, and Janine Beyer. The authors thank Saif Baig and Francisco Gimenez for their laboratory efforts associated with

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