Feasibility of Computed Tomography-Guided Methods for Spatial Normalization of Dopamine Transporter Positron Emission Tomography Image

<div><p>Background</p><p>Spatial normalization is a prerequisite step for analyzing positron emission tomography (PET) images both by using volume-of-interest (VOI) template and voxel-based analysis. Magnetic resonance (MR) or ligand-specific PET templates are currently used for spatial normalization of PET images. We used computed tomography (CT) images acquired with PET/CT scanner for the spatial normalization for [¹⁸F]-N-3-fluoropropyl-2-betacarboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) PET images and compared target-to-cerebellar standardized uptake value ratio (SUVR) values with those obtained from MR- or PET-guided spatial normalization method in healthy controls and patients with Parkinson’s disease (PD).</p><p>Methods</p><p>We included 71 healthy controls and 56 patients with PD who underwent [¹⁸F]-FP-CIT PET scans with a PET/CT scanner and T1-weighted MR scans. Spatial normalization of MR images was done with a conventional spatial normalization tool (cvMR) and with DARTEL toolbox (dtMR) in statistical parametric mapping software. The CT images were modified in two ways, skull-stripping (ssCT) and intensity transformation (itCT). We normalized PET images with cvMR-, dtMR-, ssCT-, itCT-, and PET-guided methods by using specific templates for each modality and measured striatal SUVR with a VOI template. The SUVR values measured with FreeSurfer-generated VOIs (FSVOI) overlaid on original PET images were also used as a gold standard for comparison.</p><p>Results</p><p>The SUVR values derived from all four structure-guided spatial normalization methods were highly correlated with those measured with FSVOI (<i>P</i> < 0.0001). Putaminal SUVR values were highly effective for discriminating PD patients from controls. However, the PET-guided method excessively overestimated striatal SUVR values in the PD patients by more than 30% in caudate and putamen, and thereby spoiled the linearity between the striatal SUVR values in all subjects and showed lower disease discrimination ability. Two CT-guided methods showed comparable capability with the MR-guided methods in separating PD patients from controls and showed better correlation between putaminal SUVR values and the parkinsonian motor severity than the PET-guided method.</p><p>Conclusion</p><p>CT-guided spatial normalization methods provided reliable striatal SUVR values comparable to those obtained with MR-guided methods. CT-guided methods can be useful for analyzing dopamine transporter PET images when MR images are unavailable.</p></div

Examples of spatial normalization by five different spatial normalization methods in a healthy control and a PD patient.

<p>Four structure-guided spatial normalization methods work well for normalization of PET images, and the PET-guided method also works well in healthy control. However, in PD patient the PET-guided method stretches anterior putamen posteriorly to fill the posterior putamen during the non-linear spatial normalization. Color bars are scaled in standardized uptake value ratio (SUVR). Abbreviations: cvMR = MR-guided spatial normalization with conventional normalization tool, dtMR = MR-guided spatial normalization with DARTEL toolbox, ssCT = skull-stripped CT-guided spatial normalization, itCT = intensity transformed CT-guided spatial normalization, PET = PET-guided spatial normalization.</p

Image processing steps for acquiring skull-stripped CT (ssCT) and intensity-transformed CT (itCT) templates.

<p>(a) Inhomogeneity correction and segmentation of MR, (b) creation of whole brain and CSF masks, (c) skull-stripping of inhomogeneity-corrected MR, (d) spatial normalization of skull-stripped MR to MNI template for skull-stripped MR, (e) spatial normalization of masks by applying normalization parameter, (f) creation of probabilistic maps for whole brain and CSF by averaging tissue masks, (g) coregistration of CT to inhomogeneity-corrected MR, (h) creation of skull mask, (i) spatial normalization of skull mask, (j) creation of probabilistic map for skull, (k) spatial normalization of coregistered CT, (l) creation of whole CT template by averaging, (m) creation of template mask for scalp-stripping, (n) spatial normalization of CT to whole CT template, (o) inverse normalization of template mask for scalp-stripping to create individual mask for scalp-stripping, (p) creation of scalp-stripped CT by applying mask, (q) segmentation of scalp-stripped CT into three tissue type by using probabilistic maps, (r) creation of ssCT by applying mask for whole brain segment, (s) coregistration of ssCT to MR by applying parameter coregistering original CT to MR, (t) spatial normalization of coregistered ssCT, (u) creation of ssCT template by averaging, (v) intensity transformation of original CT, (w) coregistration of itCT to MR, (x) spatial normalization of coregistered itCT, (y) creation of itCT template by averaging, and (z) spatial normalization of individual ssCT and itCT to specific CT templates. The processing steps inside the red (ssCT) and blue (itCT) dashed lines represent the image processing steps required for the spatial normalization of CT images with created CT templates.</p

Striatal SUVR values of healthy controls (HC) and Parkinson’s disease (PD) patients.

<p>Biases were calculated as the % difference between the SUVR values derived from each spatial normalization method and those measured with FSVOI. For PD patients, data are presented with the SUVR values of combined region of both sides (both), those of the regions contralateral to the clinically worse side (worse), and those of the regions contralateral to the clinically better side (better). Abbreviations: FSVOI = FreeSurfer-generated volume of interest, cvMR = MR-guided spatial normalization with conventional tool, dtMR = MR-guided spatial normalization with DARTEL toolbox, ssCT = skull-stripped CT-guided spatial normalization, itCT = intensity transformed CT-guided spatial normalization, PET = PET-guided spatial normalization</p><p>Striatal SUVR values of healthy controls (HC) and Parkinson’s disease (PD) patients.</p

Striatal standardized uptake value ratio (SUVR) values (A: caudate, B: putamen) of healthy controls (HC) and Parkinson’s disease (PD) patients.

<p>The horizontal red bars represent mean and standard deviation (SD). T- and <i>P</i>-values for comparing two groups with independent t-test are presented on the top of the graphs. Abbreviations: FSVOI = FreeSurfer-generated volume of interest, cvMR = MR-guided spatial normalization with conventional normalization tool, dtMR = MR-guided spatial normalization with DARTEL toolbox, ssCT = skull-stripped CT-guided spatial normalization, itCT = intensity transformed CT-guided spatial normalization, PET = PET-guided spatial normalization.</p

Mean and standard deviation (SD) images of each spatial normalization method and the results of voxel-based comparison between the healthy controls (HC) and Parkinson’s disease (PD) patients.

<p>For PD patients images were flipped to locate more affected side (contralateral to the clinically worse side; W) on the left (L) and the less affected side (contralateral to the clinically better side; B) on the right (R). The mean images of controls and PD patients derived from four structure-guided spatial normalization methods are similar. However, the caudate and anterior part of the putamen of PD patients were overestimated, and thereby, the mean image of PD patients derived from the PET-guided method shows higher uptake and in those regions. In contrast to the tendency shown in the mean images, the SD images of two CT-guided methods show higher SD values around the striatum, suggesting higher spatial variability. Voxel-based comparison between the controls and PD patients (family-wise error corrected) show the highest significance with the dtMR-guided method, and two CT-guided methods were inferior to the MR-guided methods. Color bars for mean and SD images represent standardized uptake value ratio (SUVR), and that for the voxel-based comparison images represents T-value for the comparison. Abbreviations: cvMR = MR-guided spatial normalization with conventional normalization tool, dtMR = MR-guided spatial normalization with DARTEL toolbox, ssCT = skull-stripped CT-guided spatial normalization, itCT = intensity transformed CT-guided spatial normalization, PET = PET-guided spatial normalization.</p

Regression analysis between the standardized uptake value ratio (SUVR) values measured with individual volume of interest (FSVOI) and those derived from five different spatial normalization methods (A and B), and correlation between the regional SUVR values and the clinical severity scores (C and D).

<p>In A and B, regression lines for each diagnostic group are presented with green (healthy controls; HC) and red (Parkinson’s disease; PD) dotted lines. Closed (HC) and open (PD) circles represent regional SUVR values of individual subjects. The R² values for regression analysis in all subjects are presented in the right lower corner of each graph. The PET-guided spatial normalization method excessively overestimates striatal SUVR values in PD patients, and results in higher discrepancy in the regression line between the controls and PD patients. In C and D, closed circles represent individual striatal SUVR values and the red lines represent regression lines. The SUVR values derived from all five spatial normalization methods are correlated with clinical severity of PD, but the statistical power is lowest for the PET-guided method. Abbreviations: FSVOI = FreeSurfer-generated volume of interest, cvMR = MR-guided spatial normalization with conventional normalization tool, dtMR = MR-guided spatial normalization with DARTEL toolbox, ssCT = skull-stripped CT-guided spatial normalization, itCT = intensity transformed CT-guided spatial normalization, PET = PET-guided spatial normalization.</p

Receiver-operator characteristic (ROC) curve analysis of striatal SUVR values derived from five different spatial normalization methods for the separation of controls and Parkinson’s disease (PD) patients.

<p>The area under the curve (AUC) values are presented in the right lower corner of each graph. Putaminal SUVR values derived from all five spatial normalization methods very effectively discriminated PD patients. Both CT-guided methods show similar performance to both MR-guided methods. However, the PET-guided method was less effective than the other four structure-guided spatial normalization methods. Abbreviations: cvMR = MR-guided spatial normalization with conventional normalization tool, dtMR = MR-guided spatial normalization with DARTEL toolbox, ssCT = skull-stripped CT-guided spatial normalization, itCT = intensity transformed CT-guided spatial normalization, PET = PET-guided spatial normalization.</p

¹⁸F-Mefway PET Imaging of Serotonin 1A Receptors in Humans: A Comparison with ¹⁸F-FCWAY

<div><p>Introduction</p><p>The purpose of this research is to evaluate the prospects for the use of 4-(<i>trans</i>-¹⁸F-fluoranylmethyl)-<i>N</i>-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-<i>N</i>-pyridin-2-ylcyclohexane-1-carboxamide (¹⁸F-Mefway) in comparison to ¹⁸F-<i>trans</i>-4-fluoro-<i>N</i>-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-<i>N</i>-(2-pyridyl)cyclohexanecarboxamide (¹⁸F-FCWAY) for the quantification of 5-HT_1A receptors in human subjects.</p><p>Method</p><p>Five healthy male controls were included for two positron emission tomography (PET) studies: ¹⁸F-FCWAY PET after the pretreatment with 500 mg of disulfiram and two months later, ¹⁸F-Mefway PET without disulfiram. Regional time-activity curves (TACs) were extracted from nine cortical and subcortical regions in dynamic PET images. Using cerebellar cortex without vermis as reference tissue, in vivo kinetics for both radioligands were compared based on the distribution volume ratio (DVR) calculated by non-invasive Logan graphical analysis and area under the curve ratio of the TACs (AUC ratio).</p><p>Result</p><p>Although the pattern of regional uptakes in the ¹⁸F-Mefway PET was similar to that of the ¹⁸F-FCWAY PET (highest in the hippocampus and lowest in the cerebellar cortex), the amount of regional uptake in ¹⁸F-Mefway PET was almost half of that in ¹⁸F-FCWAY PET. The skull uptake in ¹⁸F-Mefway PET was only 25% of that in ¹⁸F-FCWAY PET with disulfiram pretreatment. The regional DVR values and AUC ratio values for ¹⁸F-Mefway were 17—40% lower than those of ¹⁸F-FCWAY. In contrast to a small overestimation of DVR values by AUC ratio values (< 10%) in ¹⁸F-FCWAY PET, the overestimation bias of AUC ratio values was much higher (up to 21%) in ¹⁸F-Mefway PET.</p><p>Conclusion</p><p>As ¹⁸F-Mefway showed lower DVR values and greater overestimation bias of AUC ratio values, ¹⁸F-Mefway may appear less favorable than ¹⁸F-FCWAY. However, in contrast to ¹⁸F-FCWAY, the resistance to <i>in vivo</i> defluorination of ¹⁸F-Mefway obviates the need for the use of a defluorination inhibitor. Thus, ¹⁸F-Mefway may be a good candidate PET radioligand for 5-HT_1A receptor imaging in human.</p></div

Chemical structures of ¹⁸F-FCWAY and ¹⁸F-Mefway.

<p>Chemical structures of ¹⁸F-FCWAY and ¹⁸F-Mefway.</p