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 electrophysiological testing. When targeting the larger putamen, however, protocols that provide a more extensive volumetric distribution by the vector (Valles et al., 2010
) appear more clinically effective (Christine et al., 2009
; Eberling et al., 2008
) than those methods (Marks et al., 2010
; Marks et al., 2008
) that provide a more limited volume of gene expression (Ceregene, 2009
). In attempts to maximize gene therapeutic delivery to larger brain targets, such as putamen, our group has tried to better understand the volumetric differences between the human and NHP brains (Yin et al., 2009b
), to take advantage of the superior distribution characteristics afforded by CED (Bobo et al., 1994
), and to define the optimal putamenal site for stereotactic catheter placement (Yin et al., 2009a
). The optimal putamenal target site, however, is only definable by stereotactic coordinates based on the AC-PC line, since it lacks a discrete anatomic correlate on neuroimaging studies, and does not have a neurophysiological signature.
Modern stereotactic targeting often features high resolution MR imaging for direct target visualization, with or without image fusion techniques (O'Gorman et al., 2009
). The latter allow the MRI to be overlayed on/with a CT scan, from which direct measurements can be obtained. Image fusion of CT and MRI, therefore, enhances measurement precision compared to MRI alone, due to the measurement artifacts associated with MRI (Pan et al., 2007
; Snell et al., 2006
; Sumanaweera et al., 1994
). Despite the advancements afforded by imaging technology, there remain some discrepancies regarding the AC-PC distance in humans, and thereby the accuracy of targeting using AC-PC line measures alone. The average AC-PC distance in humans has been cited as 24 mm (range of 20 mm to 30 mm) (Spiegelmann, 1996
). In a historical, small comparative study looking at human AC-PC measures with ventriculography or CT, mean values were 25.3 mm (range 23 mm to 28.5 mm, SD = 1.5), and 25.2 mm (range 22 mm to 28 mm, SD = 1.7), respectively (Hariz et al., 1993
). A more recent MRI-based analysis of AC-PC length in humans with advanced PD resulted in mean values of 26.3 (range 22.9 to 29.9, SD = 1.8) (Daniluk et al., 2010
). Despite these discrepancies in mean AC-PC measures, early functional neurosurgeons were quite effective in targeting paraventricular targets (Rezai et al., 2008
). To further improve localization for many deep brain targets, such as thalamus, globus pallidus, and STN, microelectrode recording/stimulation (MER) are often used to help confirm final target location prior to permanent placement of an electrode or generation of a lesion (Ondo and Bronte-Steward, 2005
Within the putamen to date, however, electrophysiologic target localization has not been clinically applicable. The most precise way of reproducibly targeting a specified locus within the putamen, therefore, remains via stereotactic guidance. Such precision is essential to the proper volumetric delivery of a gene therapy product. The goal of this study was to better understand the scale differences in measures of the AC-PC line between three primate species (human and two NHP) using 1.5T MRI. This scale information may be effective in translating stereotactic targeting data from preclinical NHP studies into human clinical trials. We postulated that understanding the relative differences in the AC-PC distance measurement, based on MRI alone, through the Human/NHP AC-PC ratio, would provide an important translational tool for future stereotactic guidance in PD and other neurological applications. We also postulated that although the relatively limited number of subjects analyzed might limit the power of our analysis and our ability to estimate the true mean AC-PC distance value for each Species group, the ratio between Human/NHP AC-PC distances would be less likely affected, especially if the AC-PC distance variations within each Species group were small. Additionally, any MRI artifacts present in the measurement data for each Species group would be cancelled out in the ratio.
Based on this study, we determined the Human/NHP AC-PC ratio to be 2.3 with our Cynomolgus monkeys and 2.1 with our Rhesus group. While the measured mean AC-PC distances (± SD) for this study’s Species groups are 28.3±1.6 mm, 12.3±0.8 mm, and 13.8±0.7 mm, for the Human, Cynomolgus, and Rhesus groups, respectively, these Species-specific data would clearly be stronger with a larger number of subjects in each group, more diverse ages and weights represented, and equal numbers from each sex. Although the reliability of our measurements within and between observers increases the confidence that our analysis truly represents the included subjects in this study, we understand the limitations of our relatively small dataset in representing the Human and NHP populations. We find comfort in the small variation in AC-PC distance measures between our two NHP groups, despite significant age and weight ranges in the two species evaluated. Although the true Human mean AC-PC measurement varies somewhere between 20 mm and 30 mm, and in our small group of human subjects was approximately 28 mm, the Humans/NHP AC-PC ratio can be safely approximated at 2.0. We believe this ratio will be useful to investigators translating NHP distance measurements, such as stereotactic coordinates, for planning future human clinical trials the call for specific, reproducible localization within the putamen or other brain structures.
We propose using stereotactic targeting data from NHP putamen (Yin et al., 2009a
) that has been adjusted for scale differences using the Human/NHP AC-PC ratio, in future human clinical trials targeting putamen for therapeutic infusions using CED. Preliminary stereotactic (X, Y, and Z) coordinates for targeting in humans would be approximately twice (2×) the stereotactic coordinates obtained in the NHPs. Targeting other brain structures, such as thalamus and brainstem (Yin et al., 2010
), would require a similar multiplication scale factor based on the Human/NHP AC-PC ratio that we have defined. It is this definition of the scale differences in linear brain measurements between human and NHP that may enhance targeting accuracy and reproducible target coverage in future clinical trials employing CED for the treatment of PD.