Motor subtypes and clinical characteristics in sporadic and genetic Parkinson's disease groups: analysis of the PPMI cohort.

Introduction: The extensive clinical variations observed in Parkinson's disease (PD) pose challenges in early diagnosis and treatment initiation. However, genetic research in PD has significantly transformed the clinical approach to its treatment. Moreover, researchers have adopted a subtyping strategy based on homogeneous clinical symptoms to improve clinical diagnosis and treatment approaches. We conducted a study to explore clinical characteristics in genetic PD groups with motor symptom subtyping. Methods: Data was driven from the Parkinson's Progression Markers Initiative (PPMI) database. The sporadic PD (sPD) group and the genetic PD group including patients with leucine-rich kinase 2 (LRRK2) or glucosylceramidase ß (GBA) mutations were analyzed. Motor subtyping was performed using Movement Disorder Society-Unified Parkinson's disease rating scale (MDS-UPDRS) scores. I-123 FP-CIT SPECT scans were used to calculate specific binding ratios (SBRs) in the caudate and putamen. Clinical symptoms of each group were also compared. Results: MDS-UPDRS III scores were lower in the LRRK2 group, compared with the GBA and sPD group (P < 0.001), but no significant differences in striatal SBRs. The putaminal SBR value of the LRRK2 group was higher than the sPD group (P < 0.05). Within the GBA group, we observed lower SBR values in the postural instability/gait difficulty (PIGD) subtype GBA group compared to the tremor-dominant (TD) subtype GBA group (P < 0.05). The TD subtype GBA group exhibited superior putaminal SBRs compared to the TD subtype sPD group (P < 0.05). The TD subtype LRRK2 group had better putaminal SBR values (P < 0.001) and MDS-UPDRS Part III scores (P < 0.05) compared to the TD sPD group. Discussions: Our subtyping approach offers valuable insights into the clinical characteristics and progression of different genetic PD subtypes. To further validate and expand these findings, future research with larger groups and long-term follow-up data is needed. The subtyping strategy based on motor symptoms holds promise in enhancing the diagnosis and treatment of genetic PD.

Serial changes of I-123 FP-CIT SPECT binding asymmetry in Parkinson's disease: Analysis of the PPMI data.

Background: Dopaminergic denervation and motor symptoms are usually asymmetric at the onset of Parkinson's disease (PD). In this study, we estimated the asymmetry of specific binding ratio (SBR) of I-123 FP-CIT SPECT images during 4-years of follow up, to demonstrate the pattern of serial changes of asymmetry. Methods: Clinical and I-123 FP-CIT SPECT image data of 301 PD patients and 141 normal controls were reviewed from the Parkinson's Progression Markers Initiative cohort. I-123 FP-CIT SPECT images were taken at baseline, 1-, 2-, and 4-year follow up periods for PD patients, and at baseline for normal controls. Asymmetry index were calculated by two methods. Method 1, by using the ratio of absolute difference of right and left SBRs to the average SBR. Method 2, by using the ratio of absolute difference of right and left SBRs to the SBR values of age-matched normal controls. Results: Asymmetry index by method 2 revealed a more significant decrease during the 4-year follow up period, compared with method 1. The baseline asymmetry index of the putamen by method 2 showed significant correlation with the non-dominant putamen SBRs. However, there were no significant correlation with the baseline asymmetry index by method 2 and motor symptoms, cognition, nor autonomic symptoms. Conclusion: We suggest a novel asymmetry index in association to age-matched normal SBR values. This novel index could be adopted in predicting and evaluating the natural course of PD.

Clinical value of machine learning-based interpretation of I-123 FP-CIT scans to detect Parkinson's disease: a two-center study.

PURPOSE: Our aim was to develop and validate a machine learning (ML)-based approach for interpretation of I-123 FP-CIT SPECT scans to discriminate Parkinson's disease (PD) from non-PD and to determine its generalizability and clinical value in two centers. METHODS: We retrospectively included 210 consecutive patients who underwent I-123 FP-CIT SPECT imaging and had a clinically confirmed diagnosis. Linear support vector machine (SVM) was used to build a classification model to discriminate PD from non-PD based on I-123-FP-CIT striatal uptake ratios, age and gender of 90 patients. The model was validated on unseen data from the same center where the model was developed (n = 40) and consecutively on data from a different center (n = 80). Prediction performance was assessed and compared to the scan interpretation by expert physicians. RESULTS: Testing the derived SVM model on the unseen dataset (n = 40) from the same center resulted in an accuracy of 95.0%, sensitivity of 96.0% and specificity of 93.3%. This was identical to the classification accuracy of nuclear medicine physicians. The model was generalizable towards the other center as prediction performance did not differ thereby obtaining an accuracy of 82.5%, sensitivity of 88.5% and specificity of 71.4% (p = NS). This was comparable to that of nuclear medicine physicians (p = NS). CONCLUSION: ML-based interpretation of I-123-FP-CIT scans results in accurate discrimination of PD from non-PD similar to visual assessment in both centers. The derived SVM model is therefore generalizable towards centers using comparable acquisition and image processing methods and implementation as diagnostic aid in clinical practice is encouraged.

Alteration of Tremor Dominant and Postural Instability Gait Difficulty Subtypes During the Progression of Parkinson's Disease: Analysis of the PPMI Cohort.

Background: Classifying PD into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes may have several limitations, such as its diagnostic inconsistency and inability to reflect disease stage. In this study, we investigated the patterns of progression and dopaminergic denervation, by prospective evaluation at regular time intervals. Methods: 325 PD dopamine replacement drug-naïve patients (age 61.2 ± 9.7, M:F = 215:110) were enrolled. Patients were grouped into TD, indeterminant, and PIGD subtypes. Clinical parameters and I-123 FP-CIT SPECT images of each groups were analyzed and compared at baseline, 1, 2, and 4 years of follow up periods. Results: Baseline I-123 FP-CIT uptakes of the striatum were significantly higher in the TD group compared with the indeterminant group and PIGD group (p < 0.01). H & Y stage and MDS-UPDRS part III scores of the indeterminant group were significantly worse at baseline, compared with the TD and PIGD groups (p < 0.001 and p < 0.01, respectively), and MDS-UPDRS part II scores of the indeterminant group were significantly worse than the PIGD group (p < 0.001). There were no other significant differences of age, gender, weight, duration of PD, SCOPA-AUT, MOCA, usage of dopamine agonists, and levodopa equivalent daily doses at baseline. After 4 years of follow up, there were no differences of I-123 FP-CIT uptakes or clinical parameters, except for the MDS-UPDRS part II between the TD and indeterminant group (p < 0.05). The motor-subtypes were reevaluated at the 4 years period, and the proportion of patients grouped to the PIGD subtype increased. In the reevaluated PIGD group, MDS-UPDRS part II score (p < 0.001), SCOPA-AUT (p < 0.001), the proportion of patients who developed levodopa induced dyskinesia were higher than the reevaluated TD group, and the striatal I-123 FP-CIT uptakes were significantly lower (p < 0.01). Conclusion: There are no significant differences of symptoms and dopaminergic innervation between the TD and PIGD group after a certain period of follow up. Significant portion of patients switched from the TD subtype to the PIGD subtype during disease progression, and had a worse clinical prognosis.

Individual parkinsonian motor signs and striatal dopamine transporter deficiency: a study with [I-123]FP-CIT SPECT.

INTRODUCTION: Total parkinsonian motor symptom severity correlates with presynaptic striatal dopamine function in patients with Parkinson's disease. There is a lack of studies that have investigated the associations between parkinsonian motor signs and striatal dopaminergic deficiency in patients with parkinsonism of an unknown origin. Identification of specific motor signs associated with the highest likelihood of striatal dopamine deficiency could aid the differential diagnostics of parkinsonian and tremor syndromes. METHODS: In this cross-sectional clinical and imaging study, detailed motor examinations were performed for 221 patients with parkinsonism or tremor of an unknown origin immediately before dopamine transporter (DAT) [I-123]FP-CIT SPECT imaging. Region-of-interest and voxel-based methods were used to investigate striatal DAT deficiency in relation to individual motor signs. RESULTS: Upper extremity rigidity and facial expression were the only motor signs that differentiated patients with normal and abnormal striatal DAT function. The presence of any upper extremity rigidity showed the highest likelihood of DAT deficiency (OR 4.79, 95% CI 1.56-14.75, P = 0.006) followed by reduced facial expression (OR 2.14, 95% CI 1.14-4.00, P = 0.018). In patients with DAT deficits, reduced facial expression was associated with DAT deficiency specifically in the caudate nucleus, and increased upper extremity rigidity was associated with DAT loss in the dorsal putamen (FWE-corrected P < 0.05). CONCLUSIONS: Increased upper extremity muscle tone and hypomimia are independently associated with a higher likelihood of striatal hypodopaminergic imaging finding. This information can be used as a factor when the clinical need of auxiliary investigations, such as DAT SPECT, is considered for patients with parkinsonism.

Serial I-123-FP-CIT SPECT Image Findings of Parkinson's Disease Patients With Levodopa-Induced Dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a major complication of dopamine replacement drug usage in Parkinson's disease (PD) patients. Since the mechanism of LID is yet unclear, we analyzed serial [I-123] N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (I-123 FP-CIT) single photon emission computed tomography (SPECT) images. We investigated the changes of dopaminergic innervation during the progression of PD in relation to the development of LID. Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Two hundred and ninety PD dopamine replacement drug-naïve patients (age 61.0 ± 9.7, M: F = 195: 95) were enrolled. I-123 FP-CIT SPECT images from baseline, 12, 24, and 48 months were analyzed among with clinical factors. specific binding ratios (SBRs) of the striatal regions from I-123 FP-CIT SPECT images were analyzed. We used independent tests and logistic regression for analysis of LID risk association. Results: Among 290 patients, 36 patients developed LID after 48 months follow-up. Baseline MDS-UPDRS Part II and III scores were significantly higher in the PD patients with LID, compared with the PD patients without LID. Striatal SBRs were significantly lower in the PD patients with LID at baseline, 24 and 48 months (p < 0.001). Multivariate analysis revealed MDS-UPDRS Part II and putaminal SBRs at baseline and 24 months to be significantly associated with the development of LID (p < 0.001). Also, patients who developed LID at 48 months had a higher decrease rate of putaminal SBR at the 24 months (p < 0.05), and 48 months (p < 0.01) period. Conclusion: In this study, we demonstrated the serial changes of the nigrostriatal dopaminergic innervation in relationship to LID development for the first time. The deterioration rate of dopaminergic innervation was significantly higher in the PD patients who developed LID, compared with the PD patients who did not develop LID. Serial follow up I-123 FP-CIT SPECT acquisition during the course of PD could be helpful in predicting the development of LID.

Optimal ROI setting on the anatomically normalized I-123 FP-CIT images using high-resolution SPECT.

OBJECTIVE: The aim of this study is to establish the optimal regions of interest (ROIs) in anatomically normalized I-123 FP-CIT SPECT images for the quantification of dopamine transporter binding. METHODS: The subjects comprised 16 normal controls and 14 Parkinsonian patients. All of the normal control subjects underwent I-123 FP-CIT SPECT and MRI. The SPECT device used in this study was a Toshiba GCA-9300R with triple head detectors. I-123 FP-CIT (148 MBq) was intravenously administered as a bolus, and the SPECT scan started 4 h after the administration. The data were collected over 20 min for each subject, and reconstructed using a 3D-OSEM algorithm. The data were analyzed using SPM8. I-123 FP-CIT SPECT images were anatomically normalized to the MNI space using an I-123 FP-CIT template, and then divided by the background counts automatically measured using the ROIs set for the cerebral cortices. RESULTS: In the normal control subjects, the specific binding ratios of the MRI-based ROIs were lowest in the caudate nucleus, while the ratios of the I-123 FP-CIT-based ROIs were almost the same throughout all three parts. In contrast, in Parkinsonian patients, the specific binding ratios of the I-123 FP-CIT-based ROIs revealed rostrocaudal decline, while those of the MRI-based ROIs were highest in the anterior putamen. CONCLUSION: We created an ROI template on the anatomically normalized MRI and I-123 FP-CIT images, and concluded that I-123 FP-CIT-based ROIs are more suitable for obtaining quantitative values than MRI-based ones.

Creation and validation of an I-123 FP-CIT template for statistical image analysis using high-resolution SPECT for parkinsonian patients.

OBJECTIVE: The aim of this study was to create a new template for the anatomical normalization of I-123 FP-CIT SPECT images of Japanese people to evaluate dopamine transporter binding. METHODS: The subjects consisted of 16 normal control subjects (5 females and 11 males; mean age ± SD, 51.6 ± 9.5 years, ranging from 25 to 62 years) and 21 parkinsonian patients (7 females and 14 males; mean age ± SD, 70.7 ± 9.4 years, ranging from 49 to 85 years). All normal control subjects and 21 patients with parkinsonism underwent MRI. A total of 148 MBq of I-123 FP-CIT was intravenously injected as a bolus, and a SPECT scan was started 4 h later. Data were analyzed with the Statistical Parametric Mapping 8 (SPM8) software. At first, I-123 FP-CIT SPECT images were co-registered to MRI images and MRI images were normalized to Montreal Neurological Institute (MNI) space using a gray.nii template. Co-registered I-123 FP-CIT SPECT images were normalized using the predetermined normalization parameters for MRI images. Then, anatomically normalized I-123 FP-CIT SPECT images were divided by background counts individually measured using ROIs set on the cerebral cortices. The I-123 FP-CIT template was created by averaging the normalized SPECT images of the 16 normal control subjects. Thereafter, the averaged MRI images of the 16 normal control subjects were also created. RESULTS: A visual inspection revealed that there were no apparent differences between the I-123 FP-CIT images subjected to the two methods of anatomical normalization in normal control subjects. However, a group comparison by a paired t test using SPM8 revealed that the I-123 FP-CIT binding was significantly higher in the substriatal and temporal regions in I-123 FP-CIT images directly normalized with the I-123 FP-CIT template than in those normalized by the predetermined parameters with MRI, while it was higher in the bilateral frontal cortical regions in the latter than in the former images. CONCLUSION: We successfully created an I-123 FP-CIT template for Japanese people. This template is thought to be useful and reliable for the statistical analysis of I-123 FP-CIT images, although some problems exist in the evaluation of parkinsonian patients. The results of a paired t test using SPM suggest that we should use the same normalization method in statistical image analyses.