Patients
123I-FP-CIT SPECT was performed in 47 patients with suspected dNDD from June 2020 to August 2023. According to the clinical diagnostic criteria [1, 2], a comprehensive diagnosis was made by a neurologist based on patients’ cognitive impairment, psychiatric symptoms, motor dysfunction, Hoehn and Yahr scale, levodopa responsiveness, and imaging tests such as computed tomography (CT), magnetic resonance imaging, and nuclear medicine. The clinical diagnoses were 29 patients with dNDD, including 25 patients with PD and 4 patients with DLB, and 18 patients with non-dNDD, including 5 patients with ET, 5 patients with DIP, 3 patients with AD, and 5 patients with other diseases such as depression and cervical spondylosis. There were no cases of reduced DAT uptake in the striatum or parenchyma due to organic disease.
This retrospective observational study was conducted with anonymized personal information and was approved by our institutional ethics committee (approval number 0503 [2023]). Moreover, patients were given the opportunity to opt out via a notice posted in our institution.
Imaging protocol for 123I-FP-CIT SPECT/CT
SPECT/CT scans were performed using a dual-head SPECT/CT system with low-energy high-resolution collimators and 6-row detector CT (Symbia Intevo6; Siemens Healthineers, Erlangen, Germany) 4 h after intravenous injection of ~ 167 MBq of 123I-FP-CIT (Nihon Medi-Physics Co., Ltd., Tokyo, Japan).
SPECT scans were acquired with 2.4-mm pixels in a 256 × 256 matrix and 90 projections over 360° in a circular orbit of radius 14 cm with a dwell time of 40 s/frame (i.e., total acquisition time of 30 min). The energy windows were set at 159.0 keV ± 7.5% for the photopeak window and at 176.5 keV ± 3.5% and 141.5 keV ± 3.5% for the sub-window. After the SPECT acquisition, CT scans were acquired using a tube voltage of 130 kVp, detector collimation of 6 × 2.0 mm, an automatic exposure control algorithm with 100 quality reference mAs (CARE Dose 4D; Siemens Healthineers), a gantry rotation time of 1.5 s, and a pitch factor of 1.0. CT data were reconstructed with a 3.0-mm slice thickness and 300-mm field of view using a filter kernel (H31s medium; Siemens Healthineers).
SPECT data were reconstructed using a workstation (Syngo MI Applications VB20 software; Siemens Healthineers) with ordered-subset conjugate gradient minimization (OSCGM) algorithms with scatter correction using a dual-energy window approach, attenuation correction based on a CT-derived attenuation map, and depth-dependent spatial resolution correction. The reconstruction parameters were set to 1 subset and 30 iterations and a Gaussian filter with a full-width at half-maximum (FWHM) of 7.2 mm with examination type “Brain.” SPECT images were adjusted for the cerebral axis by referring to the CT images so that the transverse plane was parallel to the anterior commissure-posterior commissure line.
Striatal DAT quantitative values depend on the reconstruction parameters, and correction for scattering, attenuation, and spatial resolution reduces errors from the true value and improves accuracy [24, 25]. Therefore, we validated the optimal iterations and FWHM of the Gaussian filter in 123I-FP-CIT SPECT with application of all compensations, through preliminary physical evaluation of striatal contrast, background noise, and recovery coefficient using a striatal phantom.
Sensitivity calibration procedure for SPECT quantification
The SPECT/CT system was calibrated by planar and volume sensitivity resulting from periodic planar scanning of a syringe containing 167 MBq 123I and SPECT scanning of a cylinder phantom with a 6380-mL volume containing 40 MBq 123I, using a quantification application (Broad Quantification; Siemens Healthineers) and workstation. The actual radioactivity was measured using a dose calibrator (CRC-55t; Capintec Inc., Florham Park, NJ) and the mean count in the voxel of interest (VOI) drawn on the SPECT image was measured. The becquerel calibration factor (BCF) was calculated using Eq. 1.
$$\text{B}\text{C}\text{F} =\frac{\text{a}\text{c}\text{t}\text{u}\text{a}\text{l} \text{r}\text{a}\text{d}\text{i}\text{o}\text{a}\text{c}\text{t}\text{i}\text{v}\text{i}\text{t}\text{y}/\text{p}\text{h}\text{a}\text{n}\text{t}\text{o}\text{m} \text{v}\text{o}\text{l}\text{u}\text{m}\text{e}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{V}\text{O}\text{I}}$$
1
The radiation decay was compensated by the recorded times of the radioactivity measurement and the scans. Consequently, voxel values displayed on the workstation were converted from the γ-ray count to radioactivity concentration (Bq/mL) by the sensitivity calibration, allowing the below-mentioned SUV measurements.
Imaging analysis for DAT quantitative indices
The following striatal DAT quantitative indices were calculated by analyzing clinical SPECT/CT images. The distribution volume ratio (DVR) of DAT uptake in the caudate and putamen was measured using Scenium software (Siemens Healthineers). The analytical procedure for DVR is shown in Fig. 1. First, an original 123I-FP-CIT SPECT image or optional CT image was input into the software and then affine registered to the standard template. The standard template was created as follows: 1) affine registration of an individual 123I-FP-CIT SPECT/CT image to MNI space using SPM, deformation of the SPECT image with the resulting parameters, and normalization of the voxels by the mean uptake value in the occipital lobe; and 2) affine registration of SPECT images in diverse 123I-FP-CIT uptake groups to the normalized image and additive averaging.
Then, standard VOIs were depicted on the caudate, putamen, and occipital lobes in the original SPECT image registered to the standard template. The outline of the VOI in the DVR analysis is shown in Fig. 2a. A standard VOI was created by 1) segmenting the striatum from the standard template based on the automated anatomical labeling (AAL) atlas [18, 25]; and 2) separating the striatum into the caudate and putamen with slight enlargement, giving caudate and putamen volumes of 11 and 9 mL, respectively. The caudate-to-occipital lobe, putamen-to-occipital lobe, and striatum-to-occipital lobe ratios (COR, POR, and SOR, respectively) and the putamen-to-caudate ratio (PCR) were calculated using Eqs. 2–5.
$$\text{C}\text{O}\text{R} \text{o}\text{n} \text{D}\text{V}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} 75 \text{p}\text{e}\text{r}\text{c}\text{e}\text{n}\text{t} \text{h}\text{i}\text{g}\text{h}\text{e}\text{s}\text{t} \text{v}\text{o}\text{x}\text{e}\text{l}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{c}\text{a}\text{u}\text{d}\text{a}\text{t}\text{e} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{o}\text{c}\text{c}\text{i}\text{p}\text{i}\text{t}\text{a}\text{l} \text{l}\text{o}\text{b}\text{e} \text{V}\text{O}\text{I}}$$
2
$$\text{P}\text{O}\text{R} \text{o}\text{n} \text{D}\text{V}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} 75 \text{p}\text{e}\text{r}\text{c}\text{e}\text{n}\text{t} \text{h}\text{i}\text{g}\text{h}\text{e}\text{s}\text{t} \text{v}\text{o}\text{x}\text{e}\text{l}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{p}\text{u}\text{t}\text{a}\text{m}\text{e}\text{n} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{o}\text{c}\text{c}\text{i}\text{p}\text{i}\text{t}\text{a}\text{l} \text{l}\text{o}\text{b}\text{e} \text{V}\text{O}\text{I}}$$
3
$$\text{S}\text{O}\text{R} \text{o}\text{n} \text{D}\text{V}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} 75 \text{p}\text{e}\text{r}\text{c}\text{e}\text{n}\text{t} \text{h}\text{i}\text{g}\text{h}\text{e}\text{s}\text{t} \text{v}\text{o}\text{x}\text{e}\text{l}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{V}\text{O}\text{I} }{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{o}\text{c}\text{c}\text{i}\text{p}\text{i}\text{t}\text{a}\text{l} \text{l}\text{o}\text{b}\text{e} \text{V}\text{O}\text{I}}$$
4
$$\text{P}\text{C}\text{R} \text{o}\text{n} \text{D}\text{V}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} 75 \text{p}\text{e}\text{r}\text{c}\text{e}\text{n}\text{t} \text{h}\text{i}\text{g}\text{h}\text{e}\text{s}\text{t} \text{v}\text{o}\text{x}\text{e}\text{l}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{p}\text{u}\text{t}\text{a}\text{m}\text{e}\text{n} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} 75 \text{p}\text{e}\text{r}\text{c}\text{e}\text{n}\text{t} \text{h}\text{i}\text{g}\text{h}\text{e}\text{s}\text{t} \text{v}\text{o}\text{x}\text{e}\text{l}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{c}\text{a}\text{u}\text{d}\text{a}\text{t}\text{e} \text{V}\text{O}\text{I}}$$
5
Additionally, index asymmetries on DVR, which represent left/right differences in DAT uptake, were calculated using Eq. 6.
$$\text{A}\text{s}\text{y}\text{m}\text{m}\text{e}\text{t}\text{r}\text{y} \text{o}\text{n} \text{D}\text{V}\text{R} \left(\text{%}\right)=\frac{ \left|{\text{D}\text{V}\text{R}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} - {\text{D}\text{V}\text{R}}_{\text{l}\text{e}\text{f}\text{t}}\right|}{{(\text{D}\text{V}\text{R}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} + {\text{D}\text{V}\text{R}}_{\text{l}\text{e}\text{f}\text{t}})/2 }\times 100 \left(\%\right)$$
6
Binding ratio (BR) was measured using DaTView software (Nihon Medi-Physics Co., Ltd.), a recently updated software package. The analytical procedure for BR is also shown in Fig. 1. First, the original 123I-FP-CIT SPECT image was input into the software, and then linear and non-linear registration were performed to the standard template formed by weighted averaging of the normal and egg-shaped templates by the adaptive atlas for adaptation to the target [26]. A standard template was created by 1) registering 123I-FP-CIT SPECT and brain MRI images of the same individual, using diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) implemented in SPM; 2) registering the brain MRI image to MNI space, deforming the SPECT image with the resulting parameters, and normalizing the voxels by the mean value of the uptake in the occipital lobe; and 3) registering SPECT images in the normal and egg-like 123I-FP-CIT uptake groups to the normalized image and additive averaging.
Then, standard VOIs based on the AAL atlas [18, 25] were depicted on the caudate, putamen, and occipital lobes in the original SPECT image registered to the standard template. The outline of the VOI in the BR analysis is shown in Fig. 2b. COR, POR, SOR, and PCR were calculated using Eqs. 7–10.
$$\text{C}\text{O}\text{R} \text{o}\text{n} \text{B}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{c}\text{a}\text{u}\text{d}\text{a}\text{t}\text{e} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{o}\text{c}\text{c}\text{i}\text{p}\text{i}\text{t}\text{a}\text{l} \text{l}\text{o}\text{b}\text{e} \text{V}\text{O}\text{I}}-1$$
7
$$\text{P}\text{O}\text{R} \text{o}\text{n} \text{B}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{p}\text{u}\text{t}\text{a}\text{m}\text{e}\text{n} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{o}\text{c}\text{c}\text{i}\text{p}\text{i}\text{t}\text{a}\text{l} \text{l}\text{o}\text{b}\text{e} \text{V}\text{O}\text{I}}-1$$
8
$$\text{S}\text{O}\text{R} \text{o}\text{n} \text{B}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{o}\text{c}\text{c}\text{i}\text{p}\text{i}\text{t}\text{a}\text{l} \text{l}\text{o}\text{b}\text{e} \text{V}\text{O}\text{I}}-1$$
9
$$\text{P}\text{C}\text{R} \text{o}\text{n} \text{B}\text{R}=\frac{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{p}\text{u}\text{t}\text{a}\text{m}\text{e}\text{n} \text{V}\text{O}\text{I}}{\text{m}\text{e}\text{a}\text{n} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{c}\text{a}\text{u}\text{d}\text{a}\text{t}\text{e} \text{V}\text{O}\text{I}}$$
10
Additionally, index asymmetries on BR were calculated using Eq. 11.
$$\text{A}\text{s}\text{y}\text{m}\text{m}\text{e}\text{t}\text{r}\text{y} \text{o}\text{n} \text{B}\text{R} \left(\text{%}\right)=\frac{ \left|{\text{B}\text{R}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} - {\text{B}\text{R}}_{\text{l}\text{e}\text{f}\text{t}}\right|}{{(\text{B}\text{R}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} + {\text{B}\text{R}}_{\text{l}\text{e}\text{f}\text{t}})/2 }\times 100 \left(\%\right)$$
11
The abovementioned SBR based on Bolt’s method was measured using DaTView software [15]. Large VOIs with a slab thickness of 44.5 mm were automatically depicted at the center of the striatum and in the background. The outline of the VOI in the SBR analysis is shown in Fig. 2c. The background contour was extracted using the distance-weighted histogram method set to a FWHM of 16 mm, and the assumed striatum volume was set to 11.2 mL. SBR and its asymmetry were calculated using Eqs. 12 and 13.
$$\text{S}\text{B}\text{R}=\frac{\frac{\text{t}\text{o}\text{t}\text{a}\text{l} \text{c}\text{o}\text{u}\text{n}\text{t} \text{i}\text{n} \text{t}\text{h}\text{e} \text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{V}\text{O}\text{I} }{\text{c}\text{o}\text{u}\text{n}\text{t} \text{p}\text{e}\text{r} \text{u}\text{n}\text{i}\text{t} \text{v}\text{o}\text{l}\text{u}\text{m}\text{e} \text{i}\text{n} \text{t}\text{h}\text{e} \text{b}\text{a}\text{c}\text{k}\text{g}\text{r}\text{o}\text{u}\text{n}\text{d} \text{V}\text{O}\text{I}} - \text{v}\text{o}\text{l}\text{u}\text{m}\text{e} \text{o}\text{f} \text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{V}\text{O}\text{I}}{\text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{v}\text{o}\text{l}\text{u}\text{m}\text{e}}$$
12
$$\text{A}\text{s}\text{y}\text{m}\text{m}\text{e}\text{t}\text{r}\text{y} \text{o}\text{n} \text{S}\text{B}\text{R} \left(\text{%}\right)=\frac{ \left|{\text{S}\text{B}\text{R}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} - {\text{S}\text{B}\text{R}}_{\text{l}\text{e}\text{f}\text{t}}\right|}{{(\text{S}\text{B}\text{R}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} + {\text{S}\text{B}\text{R}}_{\text{l}\text{e}\text{f}\text{t}})/2 }\times 100 \left(\%\right)$$
13
Striatal SUV was measured using a workstation. First, VOIs were drawn and modified manually around the visible bilateral striatum. Then, the VOIs were semi-automatically adjusted to fit the striatal uptake based on the threshold maximum voxel value, defined as 65%. The outline of the VOI in the SUV analysis is shown in Fig. 2d. SUVmax, SUVmean, and their asymmetries were calculated using Eqs. 14–17.
$$\text{S}\text{U}\text{V}\text{m}\text{a}\text{x} =\frac{\text{m}\text{a}\text{x} \text{v}\text{o}\text{x}\text{e}\text{l} \text{v}\text{a}\text{l}\text{u}\text{e}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{V}\text{O}\text{I}\text{s}}{\text{a}\text{d}\text{m}\text{i}\text{n}\text{i}\text{s}\text{t}\text{r}\text{a}\text{t}\text{i}\text{o}\text{n} \text{d}\text{o}\text{s}\text{e}/\text{p}\text{a}\text{t}\text{i}\text{e}\text{n}\text{t}{\prime }\text{s} \text{w}\text{e}\text{i}\text{g}\text{h}\text{t}}$$
14
$$\text{S}\text{U}\text{V}\text{m}\text{e}\text{a}\text{n} =\frac{\text{m}\text{e}\text{a}\text{n} \text{v}\text{o}\text{x}\text{e}\text{l} \text{v}\text{a}\text{l}\text{u}\text{e}\text{s} \text{i}\text{n} \text{t}\text{h}\text{e} \text{s}\text{t}\text{r}\text{i}\text{a}\text{t}\text{u}\text{m} \text{V}\text{O}\text{I}\text{s}}{\text{a}\text{d}\text{m}\text{i}\text{n}\text{i}\text{s}\text{t}\text{r}\text{a}\text{t}\text{i}\text{o}\text{n} \text{d}\text{o}\text{s}\text{e}/\text{p}\text{a}\text{t}\text{i}\text{e}\text{n}\text{t}{\prime }\text{s} \text{w}\text{e}\text{i}\text{g}\text{h}\text{t}}$$
15
$$\text{A}\text{s}\text{y}\text{m}\text{m}\text{e}\text{t}\text{r}\text{y} \text{o}\text{n} \text{S}\text{U}\text{V}\text{m}\text{a}\text{x} \left(\text{%}\right)=\frac{ \left|{\text{S}\text{U}\text{V}\text{m}\text{a}\text{x}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} - {\text{S}\text{U}\text{V}\text{m}\text{a}\text{x}}_{\text{l}\text{e}\text{f}\text{t}}\right|}{{(\text{S}\text{U}\text{V}\text{m}\text{a}\text{x}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} + {\text{S}\text{U}\text{V}\text{m}\text{a}\text{x}}_{\text{l}\text{e}\text{f}\text{t}})/2 }\times 100 \left(\%\right)$$
16
$$\text{A}\text{s}\text{y}\text{m}\text{m}\text{e}\text{t}\text{r}\text{y} \text{o}\text{n} \text{S}\text{U}\text{V}\text{m}\text{e}\text{a}\text{n} \left(\text{%}\right)=\frac{ \left|{\text{S}\text{U}\text{V}\text{m}\text{e}\text{a}\text{n}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} - {\text{S}\text{U}\text{V}\text{m}\text{e}\text{a}\text{n}}_{\text{l}\text{e}\text{f}\text{t}}\right|}{{(\text{S}\text{U}\text{V}\text{m}\text{e}\text{a}\text{n}}_{\text{r}\text{i}\text{g}\text{h}\text{t}} + {\text{S}\text{U}\text{V}\text{m}\text{e}\text{a}\text{n}}_{\text{l}\text{e}\text{f}\text{t}})/2 }\times 100 \left(\%\right)$$
17
Statistical analysis
Statistical analysis was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Development Core Team, Vienna, Austria) [27]. Differences in patients’ characteristics and DAT quantitative values between dNDD and non-dNDD were assessed by Fisher’s exact test for nominal variables and the t-test and Welch test for continuous variables. Correlations in quantitative indices were assessed by Pearson product-moment correlation coefficients. P < 0.01 was considered statistically significant. Normality and equal variances of the data regarding the choice of statistical method were ascertained by Kolmogorov–Smirnov and F tests. Diagnostic accuracy for dNDD was determined by receiver-operating characteristic (ROC) analysis. Optimal cutoff, sensitivity, and specificity were defined by Youden’s index.