Human/nonhuman primate AC–PC ratio—Considerations for translational brain measurements
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
References (43)
- et al.
Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Life Sci
(1986) - et al.
Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach
Exp Neurol
(2000) - et al.
Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC
Mol Ther
(2006) - et al.
Real-time MR imaging of adeno-associated viral vector delivery to the primate brain
Neuroimage
(2009) - et al.
Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial
Lancet
(2007) - et al.
Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open label, phase I trial
Lancet Neurol
(2008) - et al.
Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial
Lancet Neurol
(2010) - et al.
A population-average MRI-based atlas collection of the rhesus macaque
Neuroimage
(2009) - et al.
Functional effect of adeno-associated virus mediated gene transfer of aromatic l-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats
Mol Ther
(2001) - et al.
Striatal volume differences between noh-human and human primates
J Neurosci Methods
(2009)
Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates
NeuroImage
Regression analysis: estimating relationships. Data analysis and decision making with microsoft excel
Acute and long-term effects of subthalamic nucleus stimulation in Parkinson's disease
Stereotact Funct Neurosurg
Convection-enhanced delivery of macromolecules in the brain
Proc Natl Acad Sci U S A
A phase I/II trial assessing the safety and efficacy of bilateral intraputaminal and intranigral administration of CERE-120 (adeno-associated virus serotype 2 [AAV2]–neurturin [NTN]) in subjects with idiopathic Parkinson's disease. Recombinant DNA Advisory Committee (RAC)
Safety and tolerability of putaminal gene therapy for Parkinson's disease
Neurology
Assessment of the variability in the anatomical position and size of the subthalamic nucleus among patients with advanced Parkinson's disease using magnetic resonance imaging
Acta Neurochir
Results from a phase I safety trial of hAADC gene therapy for Parkinson's disease
Neurology
Gene therapy for Parkinson's disease: from nonhuman primates to humans
Curr Opin Mol Ther
Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease
Nat Med
Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys
Brain
Cited by (12)
Posterolateral Trajectories Favor a Longer Motor Domain in Subthalamic Nucleus Deep Brain Stimulation for Parkinson Disease
2017, World NeurosurgeryCitation Excerpt :Table 1 summarizes the demographic and anatomic characteristics of these patients. The average values are aligned with the numbers reported previously in the DBS and anatomic literature.30,34-38 Men had larger third ventricles than did women (Table 2), despite a slightly younger age at surgery.
Probabilistic conversion of neurosurgical DBS electrode coordinates into MNI space
2017, NeuroImageCitation Excerpt :This additional conversion step requires knowing the AC-PC distance of the cohort, which is rarely reported (for exceptions see Papavassiliou et al., 2004; Ponce et al., 2015). The AC-PC distance varies between Talairach and MNI space, from 19 to 32 mm across single subjects, and from 24.9 to 28.3 mm across different populations (Fig. 1; Fiandaca et al., 2011; Lee et al., 2008; Liang et al., 2015; Papavassiliou et al., 2004). Moreover, the exact landmarks used to define the AC and PC themselves vary across centers (Weiss et al., 2003; Fig. 1b).
Using viral-mediated gene delivery to model Parkinson's disease: Do nonhuman primate investigations expand our understanding?
2014, Experimental NeurologyCitation Excerpt :Anatomic and functional neuroimaging in the MPTP NHP model closely correlates with the human PD condition (Valles et al., 2010), without obvious anatomical discrepancies. Anatomical imaging of NHPs for stereotactic targeting is typically performed on human magnetic resonance (MR) scanners, allows correlation to human anatomy (Fiandaca et al., 2011; Yin et al., 2009, 2010, 2011), and has been useful in preparation for human clinical PD investigations (Richardson et al., 2011a, 2011b). Positron emission tomography (PET) studies document the progressive loss of DA-ergic striatal input that correlates with clinical signs in MPTP NHP models of PD (Eberling et al., 1997, 1999; Miletich et al., 1993), similar to those seen with the human condition (Brooks et al., 1990; Morrish et al., 1995).
Guided delivery of adeno-associated viral vectors into the primate brain
2012, Advanced Drug Delivery ReviewsCitation Excerpt :Understanding these variables is essential to the translation of preclinical NHP studies into clinical trials in humans. We have made a number of quantitative comparisons between humans and NHP in order to clarify the spatial and anatomical adjustments required in this process, including consideration of relative AC-PC distances [56] and volumetric differences in striatum [57]. Together with optimal cannula placement determinations in NHP and mapping onto human brain, along with the development of new delivery hardware and software, we now have in hand an integrated AAV-based gene delivery system ready for clinical development.
Nonhuman primate models of Parkinson's disease: Improvement in the Understanding of PD progress and development of novel therapy
2021, Nonhuman Primate Models in Preclinical Research