Our MRI measurements determined the volume of the putamen to be 0.7774 ± 0.01 cm3, 0.8060 ± 0.01 cm3, and 0.5460 ± 0.01 cm3 for parkinsonian Rhesus, normal Rhesus and normal Cynomolgus monkeys, respectively, and 3.9801 ± 0.15 cm3 and 3.574 ± 0.12 cm3 for PD patients and normal healthy individuals, respectively. There were no significant differences noted between right and left hemispheres in any subjects. We also found that the volumetric ratio for the putamen was 5.12:1 for parkinsonian patients vs Rhesus monkeys, and 4.43:1 and 6.55:1 for normal human individuals vs Rhesus and Cynomolgus monkeys, respectively. Normal humans were almost 8 years of age older, on average, than the PD patients. In patients over age 60, one might expect a significant decline in brain volume. Similarly, normal aged Rhesus monkeys averaged 5.4 years of age, whereas the parkinsonian Rhesus and Cynomolgus averaged 6.9 years of age. Nevertheless, the ratios that we obtained predict a roughly 5:1 difference in volume of the human vs non-human primate putamen. As such, a putaminal Vi for CED in the non-human primate, would be multiplied by 5 for potential Vi into a human putamen, if similar CED delivery parameters are employed.
CED is being applied clinically to the treatment of neurodegenerative disorders, such as PD (Eberling et al., 2008
; Gill et al., 2003
) and brain malignancies (Kunwar, 2003
; Mardor et al., 2001
). It is essential for efficacy to cover the entire targeted treatment volume while avoiding adjacent regions of the brain or CSF pathways. It has been very difficult to predict the volume of infusion (Vi) of therapeutics delivered by CED due to a lack of knowledge of volume of distribution (Vd) under these circumstances. This is true for delivery of chemotherapeutic agents to brain tumors, and for infusion of growth factors, enzymes, and viral vectors in PD patients. MRI allows the putamen and caudate nucleus to be visualized with great precision, and enables us to understand the associated volumes of the structures to be convected (infused by CED), thereby improving the accuracy of the CED procedure, provided that the Vd and Vi for the particular therapeutic within that structure are known. Volumetric differences of brain structures between non-human primates and humans provides a basis for prediction of appropriate Vi in patients based on preclinical non-human primate data. This knowledge is also critical when calculating dose of therapeutic agents such as proteins or viral vectors to be delivered to human striatum.
Under the best circumstances, targeting and delivery of therapeutics in the CNS can now be performed with the aid of real-time MRI imaging. These imaging modalities may markedly impact future neurosurgical treatments of neurodegenerative and neuro-oncologic diseases, by allowing more accurate, monitored delivery of therapeutics (Bobo et al., 1994
; Hadaczek et al., 2006
; Krauze et al., 2006
; Krauze et al., 2005a
; Krauze et al., 2005b
; Saito et al., 2005
). It has been proposed that such direct scrutiny of these treatments will increase efficacy and reduce morbidity. For the short-term, however, intra-operative MRI imaging remains a modality available to a limited number of large medical centers.
In previous reports, regional morphological changes in the brain of PD patients and healthy subjects have been studied (Duguid et al., 1986
; Hutchinson and Raff, 2000
; Lisanby et al., 1993
; O’Neill et al., 2002
; Schulz et al., 1999
). However, comparison of striatal volume by MRI in non-human primates and humans has not been reported so far. By means of MR imaging of the live brain in our studies, we have avoided the artifacts of histological processing on the brain parenchyma previously noted by others (Harman and Carpenter, 1950
; Schroder et al., 1975
). In the present study, we employed MRI data to perform volume measurements of putamen, caudate, and total brain, and to compare the volume difference of the structures and generate volumetric ratios for these structures between non-human primates and humans. Unfortunately, MRI volumetric determinations have their own associated potential errors (Pan et al., 2007
; Snell et al., 2006
; Sumanaweera et al., 1994
). We have minimized these volumetric errors in our study through the use of updated software on the MRI scanners to minimize scanner-induced magnetic field heterogeneous distortion or gradient field nonlinearity distortion (Sumanaweera et al., 1994
). Also, since our volumetric structures are located within the brain parenchyma, without large differences in tissue magnetic susceptibility, magnetic field heterogeneous distortion induced by the imaged structure’s environment does not come into play (as it would in the measurement of structures at the skull base, where there is an air/brain/bone boundary). In addition, all of our volumetric calculations have been carried out using multiple MRI slices, which have been shown to reduce PACS-associated errors (Pan et al., 2007
; Snell et al., 2006
). All our volumes measured were > 0.5 cm3
, making PACS volumetric measurements robust, with low associated error when combined with multiple MRI slices (Pan et al., 2007
). Finally, errors present using our volumetric MRI measurements would have been similar in all of our data. While absolute volume data can be affected by error, the volumetric ratios between NHP and humans would remain valid. Despite these limitations, this is the first study to perform detailed comparative quantitative analyses of striatal structures by MRI, in preparation for additional translational designs of clinical CED therapy for PD patients, based on non-human primate studies.
In summary, the present study provides the first comparative quantitative analysis by MRI of striatal volume in humans and non-human primates, including putamen and caudate nucleus. These data have significant implications for the design of future clinical trials featuring CED of various therapeutic agents into the putamen for PD. Volumetric data developed from our translational non-human primate studies, related to Vd and Vi of various therapeutics delivered via CED into the putamen, can be scaled up to the human by a factor of 5. Although further volumetric studies and in vivo real-time MRI CED infusions will be carried out to further refine the volumetric data, we are confident in reporting these volumetric differences in the striatum of humans and non-human primates.