A PET-MRI registration technique for PET studies of the rat brain¹☆,

The goal of this work is to quantify the binding parameters of [¹⁸F]Fallypride in the striatal and extrastriatal regions of the rat brain using factor analysis (FA) to correct small animal PET kinetic imaging for spillover defluorination radioactivity. Eleven rats were employed for YAP-(S)PET acquisitions and metabolite studies. All kinetic parameters including B^′_max and K_dV_R were estimated with a three-tissue compartment seven-parameter model (3T-7k) on the basis of all the FA-corrected data from the multi-injection protocol. Binding potential (BP_ND) was calculated with Logan's graphical analysis taking cerebellum as the reference region and using the first injection raw (BP_ND-RAW) and FA-corrected (BP_ND-FA) data. Three distinct factors corresponding to free + non-specific binding, specific binding and skull and gland accumulation were recovered from FA with their corresponding spatial distributions. The resulting reconstructed images without skull and gland accumulation were improved to provide a better contrast between specific and non-specific regions. Very bad fits were obtained when using time–activity curves (TACs) calculated from the raw [¹⁸F]Fallypride data, whereas all TACs were well fitted by the 3T-7k model after FA correction. FA-corrected data enables the cerebellar region to be used as reference for the Logan approach. The magnitude of the BP_ND-FA values was increased from 21% to 108% across regions and the rank order of BP_ND-FA values (Cx < Hip < MB ≈ Thal < VST < DST) matched those of B^′_max values. This [¹⁸F]Fallypride study in rats shows that all brain regions are contaminated by skull and gland radioactivity accumulation. We show that FA is a very effective method of correcting kinetic data for spillover activity. Moreover, the approach presented here with [¹⁸F]Fallypride data can be extended to other radioligands and also to human data which can be highly distorted by radiodefluorination as shown in the literature.

Anatomical standardization (also called spatial normalization) of positron emission tomography (PET) small animal brain images is required to make statistical comparisons across individuals. Frequently, PET images are co-registered to an individual MR or CT image of the same subject in order to transform the functional images to an anatomical space. In the present work, we evaluate the normalization of synthetic PET (synPET) images to a synthetic PET template. To provide absolute error in terms of pixel misregistration, we created a synthetic PET image from the individual MR image through segmentation of the brain into gray and white matter which produced functional and anatomical images in the same space. When comparing spatial normalization of synPET images to a synPET template with the gold standard (MR images to an MR template), a mean translation error of 0.24 mm (±0.20) and a maximal mean rotational error of 0.85° (±0.91) were found. Significant decrease in misregistration error was measured when achieving spatial normalization of functional images to a functional template instead of an anatomical template. This accuracy strengthens the use of standardization methods where individual PET images are registered to a customized PET template in order to statistically assess physiological changes in rat brains.

An automated method for placement of 3D rat brain atlas-derived volumes of interest (VOIs) onto PET studies has been designed and evaluated. VOIs representing major structures of the rat brain were defined on a set of digitized cryosectioned images of the rat brain. For VOI placement, each PET study was registered with a synthetic PET target constructed from the VOI template. Registration was accomplished with an automated algorithm that maximized the mutual information content of the image volumes. The accuracy and precision of this method for VOI placement was determined using datasets from PET studies of the striatal dopamine and hippocampal serotonin systems. Each evaluated PET study could be registered to at least one synthetic PET target without obvious failure. Registration was critically dependent upon the initial position of the PET study relative to the synthetic PET target, but not dependent on the amount of synthetic PET target smoothing. An evaluation algorithm showed that resultant radioactivity concentration measurements of selected brain structures had errors = 2% due to misalignment with the corresponding VOI. Further, radioligand binding values calculated from these measurements were found to be more precise than those calculated from measurements obtained with manually drawn regions of interest (ROIs). Overall, evaluation results demonstrated that this atlas-derived VOI method can be used to obtain unbiased measurements of radioactivity concentration from PET studies. Its automated features, and applicability to different radioligands and brain regions, will facilitate quantitative rat brain PET assessment procedures.

Overexpression of dopamine D₂ receptors by adenoviral vector-mediated gene transfer in the rat striatum was evaluated by positron emission tomography in vivo and by ex vivo autoradiography in 5-, 13-, and 24-month-old Fischer 344 rats. Each rat had hemilateral gene transfer of D₂ receptors mediated by adenoviral vectors (AdCMV.DopD₂R) in the striatum with contralateral striatal injection of control vectors (AdCMV.LacZ). At day 2 or 3 after vector injection positron emission tomography or ex vivo autoradiography was performed. The binding potential of a radiolabeled D₂ receptors ligand, [¹¹C]raclopride, was significantly higher in the D₂ receptors gene-transferred striatum than the control side in each age group at a similar degree. The binding potential in the AdCMV.DopD₂R-injected striatum of 24-month-old rats was similar to that in the AdCMV.LacZ-injected striatum of 5-month-old rats (0.99±0.14 versus 0.91±0.08). A significant age-associated decrease of the binding potential of [¹¹C]raclopride was found in the control vector-injected side, and a significant increase of the binding potential in the adenoviral vector-injected side in all three age groups, suggesting no aging effect on the overexpression of D₂ receptors. A group of rats underwent follow-up assessment by positron emission tomography. The overexpression of D₂ receptors decreased with time in all three groups; however, the decrease rate of the D₂ receptors expression was significantly smaller in the 24-month-old group than in the 5-month-old group. We confirmed that the adenoviral vector-mediated gene transfer of D₂ receptors compensated the decreased density of striatal D₂ receptors in the 24-month-old rats up to the level in the control striatum of 5-month-old rats, and the decrease rate of the overexpression was significantly smaller in aged rats.

With [¹¹C]raclopride,[¹¹C]nemonapride and [¹¹C]N-methylspiperone, degeneration of dopamine D₂-like receptors in the unilaterally quinolinic acid-lesioned rats was evaluated by positron emission tomography (PET) and ex vivo and in vitro autoradiography. PET showed a decreased uptake of [¹¹C]raclopride in the lesioned striatum, but an increased uptake of [¹¹C]nemonapride and [¹¹C]N-methylspiperone despite a decreased binding in vitro. Ex vivo autoradiography showed an increased accumulation of the three ligands in the cortical region overlying the injured striatum, probably enlarging PET signals. PET has the limited potential for evaluating the receptor degeneration in the present animal model.