Robustness of radiomic features in 123I-ioflupane-dopamine transporter single-photon emission computer tomography scan.

Radiomic features are usually used to predict target variables such as the absence or presence of a disease, treatment response, or time to symptom progression. One of the potential clinical applications is in patients with Parkinson's disease. Robust radiomic features for this specific imaging method have not yet been identified, which is necessary for proper feature selection. Thus, we are assessing the robustness of radiomic features in dopamine transporter imaging (DaT). For this study, we made an anthropomorphic head phantom with tissue heterogeneity using a personal 3D printer (polylactide 82% infill); the bone was subsequently reproduced with plaster. A surgical cotton ball with radiotracer (123I-ioflupane) was inserted. Scans were performed on the two-detector hybrid camera with acquisition parameters corresponding to international guidelines for DaT single photon emission tomography (SPECT). Reconstruction of SPECT was performed on a clinical workstation with iterative algorithms. Open-source LifeX software was used to extract 134 radiomic features. Statistical analysis was made in RStudio using the intraclass correlation coefficient (ICC) and coefficient of variation (COV). Overall, radiomic features in different reconstruction parameters showed a moderate reproducibility rate (ICC = 0.636, p <0.01). Assessment of ICC and COV within CT attenuation correction (CTAC) and non-attenuation correction (NAC) groups and within particular feature classes showed an excellent reproducibility rate (ICC > 0.9, p < 0.01), except for an intensity-based NAC group, where radiomic features showed a good repeatability rate (ICC = 0.893, p <0.01). By our results, CTAC becomes the main threat to feature stability. However, many radiomic features were sensitive to the selected reconstruction algorithm irrespectively to the attenuation correction. Radiomic features extracted from DaT-SPECT showed moderate to excellent reproducibility rates. These results make them suitable for clinical practice and human studies, but awareness of feature selection should be held, as some radiomic features are more robust than others.

Practical Overview of 123I-Ioflupane Imaging in Parkinsonian Syndromes.

Parkinsonian syndromes are a heterogeneous group of progressive neurodegenerative disorders involving the nigrostriatal dopaminergic pathway and are characterized by a wide spectrum of motor and nonmotor symptoms. These syndromes are quite common and can profoundly impact the lives of patients and their families. In addition to classic Parkinson disease, parkinsonian syndromes include multiple additional disorders known collectively as Parkinson-plus syndromes or atypical parkinsonism. These are characterized by the classic parkinsonian motor symptoms with additional distinguishing clinical features. Dopamine transporter SPECT has been developed as a diagnostic tool to assess the levels of dopamine transporters in the striatum. This imaging assessment, which uses iodine 123 (123I) ioflupane, can be useful to differentiate parkinsonian syndromes caused by nigrostriatal degeneration from other clinical mimics such as essential tremor or psychogenic tremor. Dopamine transporter imaging plays a crucial role in diagnosing parkinsonian syndromes, particularly in patients who do not clearly fulfill the clinical criteria for diagnosis. Diagnostic clarification can allow early treatment in appropriate patients and avoid misdiagnosis. At present, only the qualitative interpretation of dopamine transporter SPECT is approved by the U.S. Food and Drug Administration, but quantitative interpretation is often used to supplement qualitative interpretation. The authors provide an overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are also briefly discussed. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Intenzo and Colarossi in this issue.

Quantitative [123]I-Ioflupane DaTSCAN single-photon computed tomography-computed tomography in Parkinsonism.

AIM: [123]I-Ioflupane (DaTSCAN) binds to the presynaptic dopamine transporter (DAT) and with a lower affinity to the serotonin transporter (SERT). We aimed to develop a novel method to quantify absolute uptake in the striatal (predominantly DAT binding) and extra-striatal regions (mainly SERT binding) using single-photon computed tomography-computed tomography (SPECT-CT) DaTSCAN and to improve DaTSCAN image quality. METHOD: Twenty-six patients with Parkinsonism underwent DaTSCAN SPECT-CT prospectively. The scans were visually analyzed independently by two experienced reporters. Specific binding ratios (SBRs) from Chang attenuation corrected SPECT were obtained using GE DaTQuant. Normalized concentrations and specific uptakes (NSU) from measured attenuation and modelled scatter-corrected SPECT-CT were obtained using HERMES Hybrid Recon and Affinity and modified EARL volumes of interest. RESULTS: Striatal NSU and SBR positively correlate ( R  = 0.65-0.88, P  = 0.00). SBR, normalized concentrations, and NSU box plots differentiated between scans without evidence of dopaminergic deficit and abnormal scans. Interestingly, body weight inversely correlated with normalized concentrations values in extra-striatal regions [frontal ( R  = 0.81, P  = 0.00); thalamus ( R  = 0.58, P  = 0.00); occipital ( R  = 0.69, P  = 0.00)] and both caudate nuclei [ R  = 0.42, P  = 0.03 (Right), R  = 0.52, P  = 0.01 (Left)]. Both reporters noted improved visual quality of SPECT-CT versus SPECT images for all scans. CONCLUSION: DaTSCAN SPECT-CT resulted in more accurate quantification, improved image quality, and enabled absolute quantification of extra-striatal regions. More extensive studies are required to establish the full value of absolute quantification for diagnosis and monitoring the progression of neurodegenerative disease, to assess an interplay between DAT and SERT, and to verify whether serotonin and DATs are potentially dysfunctional in obesity.

Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.

BACKGROUND: It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD). OBJECTIVE: To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD. METHODS: This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group. RESULTS: From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation. CONCLUSIONS: Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

Novel approaches of erythrosine B as a food dye-derived spectroscopic probe for assessing trospium chloride in raw material and dosage form.

Two facile spectroscopic methodologies were designed for estimating trospium chloride (TPM) in raw material and tablets with high operational reliability and selectivity. The methods were based on using erythrosine B (EB) as a spectroscopic tool for ion-pair complex formation with the drug. In a mild acidic medium of Britton Robinson buffer (pH 4.0), the ionized hydroxyl group in the reagent interacted with the ionized amine in the studied drug. Method I was based on the spectrophotometric measuring of the absorbance of the reaction product at 557 nm. Method II was based on spectrofluorimetric measurement of the quenching effect of TPM on the inherent fluorescence of EB at 550 nm (λex. = 528 nm). The two methods showed linearity through ranges 1.0-10.0 and 0.5-10.0 µg/ml for Methods I and II, respectively. The suggested methods were exploited for analyzing TPM in Trospamexin® tablets and showed good applicability. The designed systems were validated as per International Conference on Harmonization guidelines. Experimental conditions were modulated to obtain the best sensitivities. The quenching mechanism was investigated and the quenching constant was computed relying on the Stern-Volmer equation. Environmental impact was appraised using novel metric green tools, GABI, and AGREE. The suggested systems excelled over other reported methods in terms of greenness, sensitivity, and cost-effectiveness.

Diagnosis of Parkinson syndrome and Lewy-body disease using 123I-ioflupane images and a model with image features based on machine learning.

OBJECTIVES: 123I-ioflupane has been clinically applied to dopamine transporter imaging and visual interpretation assisted by region-of-interest (ROI)-based parameters. We aimed to build a multivariable model incorporating machine learning (ML) that could accurately differentiate abnormal profiles on 123I-ioflupane images and diagnose Parkinson syndrome or disease and dementia with Lewy bodies (PS/PD/DLB). METHODS: We assessed 123I-ioflupane images from 239 patients with suspected neurodegenerative diseases or dementia and classified them as having PS/PD/DLB or non-PS/PD/DLB. The image features of high or low uptake (F1), symmetry or asymmetry (F2), and comma- or dot-like patterns of caudate and putamen uptake (F3) were analyzed on 137 images from one hospital for training. Direct judgement of normal or abnormal profiles (F4) was also examined. Machine learning methods included logistic regression (LR), k-nearest neighbors (kNNs), and gradient boosted trees (GBTs) that were assessed using fourfold cross-validation. We generated the following multivariable models for the test database (n = 102 from another hospital): Model 1, ROI-based measurements of specific binding ratios and asymmetry indices; Model 2, ML-based judgement of abnormalities (F4); and Model 3, features F1, F2 and F3, plus patient age. Diagnostic accuracy was compared using areas under receiver-operating characteristics curves (AUC). RESULTS: The AUC was high with all ML methods (0.92-0.96) for high or low uptake. The AUC was the highest for symmetry or asymmetry with the kNN method (AUC 0.75) and the comma-dot feature with the GBT method (AUC 0.94). Based on the test data set, the diagnostic accuracy for a diagnosis of PS/PD/DLB was 0.86 ± 0.04 (SE), 0.87 ± 0.04, and 0.93 ± 0.02 for Models 1, 2 and 3, respectively. The AUC was optimal for Model 3, and significantly differed between Models 3 and 1 (p = 0.027), and 3 and 2 (p = 0.029). CONCLUSIONS: Image features such as high or low uptake, symmetry or asymmetry, and comma- or dot-like profiles can be determined using ML. The diagnostic accuracy of differentiating PS/PD/DLB was the highest for the multivariate model with three features and age compared with the conventional ROI-based method.

Deep learning based low-activity PET reconstruction of [11C]PiB and [18F]FE-PE2I in neurodegenerative disorders.

PURPOSE: Positron Emission Tomography (PET) can support a diagnosis of neurodegenerative disorder by identifying disease-specific pathologies. Our aim was to investigate the feasibility of using activity reduction in clinical [18F]FE-PE2I and [11C]PiB PET/CT scans, simulating low injected activity or scanning time reduction, in combination with AI-assisted denoising. METHODS: A total of 162 patients with clinically uncertain Alzheimer's disease underwent amyloid [11C]PiB PET/CT and 509 patients referred for clinically uncertain Parkinson's disease underwent dopamine transporter (DAT) [18F]FE-PE2I PET/CT. Simulated low-activity data were obtained by random sampling of 5% of the events from the list-mode file and a 5% time window extraction in the middle of the scan. A three-dimensional convolutional neural network (CNN) was trained to denoise the resulting PET images for each disease cohort. RESULTS: Noise reduction of low-activity PET images was successful for both cohorts using 5% of the original activity with improvement in visual quality and all similarity metrics with respect to the ground-truth images. Clinically relevant metrics extracted from the low-activity images deviated < 2% compared to ground-truth values, which were not significantly changed when extracting the metrics from the denoised images. CONCLUSION: The presented models were based on the same network architecture and proved to be a robust tool for denoising brain PET images with two widely different tracer distributions (delocalized, ([11C]PiB, and highly localized, [18F]FE-PE2I). This broad and robust application makes the presented network a good choice for improving the quality of brain images to the level of the standard-activity images without degrading clinical metric extraction. This will allow for reduced dose or scan time in PET/CT to be implemented clinically.

[Long-term safety and efficacy of trospium chloride for the treatment of neurogenic overactive bladder due to Parkinson's disease is there an effect on cognitive status?]

AIM: To evaluate the efficiency of long-term use of trospium chloride (Spazmex) for the treatment of patients with neurogenic overactive bladder due to Parkinson's disease (PD) and to determine the influence of therapy on the cognitive status of patients. MATERIALS AND METHODS: 60 patients with PD and neurogenic overactive bladder with stages 2.5, 3 and 4 according to Hoehn-Yahr scale were included in the main group. The mean age was 58.2+/-5.7 years. All patients were prescribed trospium chloride at entry into the study, with doses titrated gradually according to clinical efficacy (30 to 90 mg). The comparison group included 15 patients with PD and neurogenic overactive bladder at stages 2,5 and 3, who received tibial neuromodulation according to the standard technique with skin electrodes. The mean age of patients was 56.4+/-4.6 years. At baseline, both groups were comparable in terms of gender, age and cognitive status (p=0.801). All patients received treatment for 52 weeks. The efficiency of therapy was assessed according to bladder diaries, while safety outcomes included postvoid residual, side effects, cognitive status according to the MoCA scale and quality of life according to the SF-Qualiveen questionnaire. RESULTS: clinical efficacy and satisfaction were achieved in all patients who completed the study (47 patients in the main group and 15 patients in the comparison group). Good clinical efficacy was demonstrated in both groups, since there was a decrease in the number of urinations, episodes of urgency and urinary incontinence. In addition, there was an improvement in the quality of life according to the SF-Qualiveen scale. The cognitive status during the entire follow-up period remained without significant changes in both groups. CONCLUSION: Trospium chloride is an effective drug in patients with PD. It does not affect cognitive functions during long-term use. Trospium chloride should be considered as first-line drug in those with urologic manifestations of PD.

N-acetylcysteine decreases dopamine transporter availability in the non-lesioned striatum of the 6-OHDA hemiparkinsonian rat.

This study aimed to explore the beneficial effects of the antioxidant N-acetylcysteine (NAC) on the degenerated dopamine system. The short- and long-term regulatory mechanisms of NAC on the 6-OHDA hemiparkinsonian rat model were longitudinally investigated by performing positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) radioligand [18F]FE-PE2I. The results demonstrate that after a unilateral dopamine insult NAC has a strong influence on the non-lesioned hemisphere by decreasing the levels of DAT in the striatum early after the lesion. We interpret this early and short-term decrease of DAT in the healthy striatum of NAC-treated animals as a beneficial compensatory effect induced by NAC.

[Neurogenic overactive bladder: focus on cognitive function].

BACKGROUND: An overactive bladder and cognitive impairment are two medical and social problems, which have an outmost importance, affecting the quality of life. Both disorders are common in the practice of a urologist, neurologist, internist, and other physicians. Parkinsons disease and multiple sclerosis are the most common neurological diseases, which often manifest by pelvic dysfunction and cognitive dysfunction. The clinician needs to understand the pathogenesis of the underlying disease and the pharmacologic properties of drugs, which can be used both in neurology and urology, as well as in other related specialties. AIM: To evaluate cognitive functions in patients with neurogenic overactive bladder treated with trospium chloride. MATERIALS AND METHODS: A total of 45 patients with neurological disease (28 with Parkinsons disease [group 1] and 17 with multiple sclerosis [group 2]) were included in the study. All patients had symptoms of an overactive bladder. Trospium chloride was administered in an individually adjusted dose for 12 weeks. Cognitive functions were assessed using the international Montreal Cognitive Assessment (MoCA) before and after the therapy. A change of total scores over time was assessed using the paired Wilcoxon test. The level of significance of <0.05 was used (confidence level of 95%). RESULTS: A significant decrease in all studied parameters of an overactive bladder in both groups was seen. The baseline evaluation of the total score on the MoCA scale prior to the start of taking trospium chloride revealed the presence of moderate cognitive impairment (21.3+/-2.9 points) in patients of the group 1. After 12 weeks of therapy, no significant change in cognitive functions was observed (21.7+/-3.1 points; p>0.05). In group 2, moderate cognitive impairment (MoCA 22.5+/-3.7 points) was found at baseline. After taking trospium chloride, no significant changes were noted (MoCA 22.9+/-4.1 points) (p>0.05). No central nervous system side effects were reported in any group. CONCLUSION: Trospium chloride is an effective drug, which does not affect cognitive functions in patients with neurogenic overactive bladder. This drug is safe to use in both Parkinsons disease and multiple sclerosis, considering the low risk of cognitive impairment in polypharmacy.

Predicting Neuropsychiatric Symptoms of Parkinson's Disease with Measures of Striatal Dopaminergic Deficiency.

BACKGROUND: The role of nigrostriatal dopaminergic neurons degeneration is well established in the pathophysiology of Parkinson's disease. However, it is unclear if and how the degeneration of the dopamine pathways affects the manifestation of the neuropsychiatric symptoms (NPS) of Parkinson's Disease (PD). Dopamine transporter (DAT) imaging, a technique to measure the reduction in dopamine transporters is increasingly used as a tool in the diagnosis of PD. METHODS: In this study, we examine if the baseline dopamine transporter density in the striatum measured by the Striatal Binding Ratio (SBR) is associated with the longitudinal onset and/or progression of NPS in PD as measured by part 1 of Movement Disorder Society - Unified Parkinson's Disease Rating Scale, over four years. Data of patients with PD and an abnormal screening present on 123I-ioflupane single-proton emission computed tomography were obtained from Parkinson's Progression Markers Initiative (PPMI) database. Latent Growth Modeling (LGM), a statistical technique that can model the change over time while considering the variability in the rate of change at the individual level, was used to examine the progression of NPS over time. RESULTS: The results indicate the SBR did not correlate with the baseline NPS but did correlate with the rate of change of NPS (p<0.001) over the next four years, even after eliminating age-related variance, which can be a significant confounding factor. CONCLUSION: In conclusion, this study showed gradual worsening in NPS in patients with Parkinson's disease, which inversely correlates with the density of the dopamine transporters as measured by SBR at baseline.

Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.

123I-Ioflupane SPECT and 18F-FDG PET Combined Use in the Characterization of Movement and Cognitive Associated Disorders in Neurodegenerative Diseases.

BACKGROUND: Both movement (MD) and cognitive (CD) disorders can occur associated in some neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). OBJECTIVE: We further investigated the usefulness of 123I-Ioflupane SPECT and 18F-FDG PET combined use in patients with these disorders in the early stage. METHODS: We retrospectively enrolled twenty-five consecutive patients with MD and CD clinical symptoms of recent appearance. All patients had undergone neurologic examination, neuropsychological tests, and magnetic resonance imaging. 123I-Ioflupane SPECT was performed in all cases, followed by 18F-FDG PET two weeks later. In the two procedures, both qualitative (QL) and quantitative (QN) image analyses were determined. RESULTS: In patients with both 123I-Ioflupane SPECT and 18F-FDG PET pathologic data, associated dopaminergic and cognitive impairments were confirmed in 56% of cases. Pathologic SPECT with normal PET in 16% of cases could diagnose MD and exclude an associated CD, despite clinical symptoms. On the contrary, normal SPECT with pathologic PET in 28% of cases could exclude basal ganglia damage while confirming CD. QN 123I-Ioflupane SPECT analysis showed better performance than QL since QN correctly characterized two cases of MD with normal QL. Moreover, correct classification of normal metabolism was made only by QN analysis of 18F-FDG PET in four cases, despite suspect areas of hypometabolism at QL. CONCLUSION: The combined use of these imaging procedures proved a reliable diagnostic tool to accurately identify and characterize MD and CD in early stage. QN analysis was effective in supporting QL evaluation, and its routine use is suggested, especially with inconclusive QL.

Hyoscyamus albus nortropane alkaloids reduce hyperglycemia and hyperinsulinemia induced in HepG2 cells through the regulation of SIRT1/NF-kB/JNK pathway.

BACKGROUND: Chronic superphysiological glucose and insulin concentrations are known to trigger several tissue and organ failures, including insulin resistance, oxidative stress and chronic low-grade inflammation. Hence, the screening for molecules that may counteract such conditions is essential in current existing therapeutic strategies, thereby the use of medicinal plant derivatives represents a promising axis in this regard. METHODS: In this study, the effect of a selected traditional medicinal plant, Hyoscyamus albus from which, calystegines have been isolated, was investigated in an experimental model of hyperinsulinemia and hyperglycemia induced on HepG2 cells. The mRNA and protein expression levels of different insulin signaling, gluconeogenic and inflammatory pathway- related molecules were examined. Additionally, cell viability and apoptosis, oxidative stress extent and mitochondrial dysfunctions were assayed using flow cytometric and qRT-PCR techniques. RESULTS: Treatment of IR HepG2 cells with calystegines strongly protected the injured cells from apoptosis, oxidative stress and mitochondrial integrity loss. Interestingly, nortropane alkaloids efficiently regulated the impaired glucose metabolism in IR HepG2 cells, through the stimulation of glucose uptake and the modulation of SIRT1/Foxo1/G6PC/mTOR pathway, which is governing the hepatic gluconeogenesis. Furthermore, the alkaloidal extract restored the defective insulin signaling pathway, mainly by promoting the expression of Insr at the mRNA and protein levels. What is more, treated cells exhibited significant mitigated inflammatory response, as evidenced by the modulation and the regulation of the NF- κB/JNK/TLR4 axis and the downstream proinflammatory cytokines recruitment. CONCLUSION: Overall, the present investigation demonstrates that calystegines from Hyoscyamus albus provide cytoprotection to the HepG2 cells against insulin/glucose induced insulin resistance and apoptosis due to the regulation of SIRT1/Foxo1/G6PC/mTOR and NF-κB/JNK/TLR4 signaling pathways. Video Abstract.

The relationship between lower urinary tract function and 123ioflupane scintigraphy in drug-naïve Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is the most common degenerative cause of movement disorder, and autonomic dysfunction has been recognized in this disorder. PD patients' lower urinary tract (LUT) function is not established. We investigated LUT function in PD by single-photon emission computerized tomography (SPECT) imaging of the dopamine transporter with 123I-ioflupane and clinical-urodynamic observations. PATIENTS AND METHODS: We retrospectively analyzed the cases of 30 patients diagnosed with PD based on published criteria who completed a systematized lower urinary tract symptoms (LUTS) questionnaire and a urodynamics examination irrespective of the presence of LUTS. None of the patients were taking anti-parkinsonian medication during the study. RESULTS: The questionnaire revealed that all 30 patients had LUTS: night-time urinary frequency (in 70%), urinary incontinence (40%), and daytime urinary frequency (80%). A urodynamic study revealed a mean volume at the first sensation at 92.3 ml, bladder capacity at 200.9 ml, and detrusor overactivity in 50%. Sphincter electromyography revealed neurogenic change in 13.6% of those for whom the test was performed. The average SBR showed a significant correlation with bladder capacity (Spearman's correlation coefficient p = 0.0076) and Hoehn Yahr motor stage (Spearman's correlation coefficient p = 0.012). CONCLUSION: Our findings demonstrate that the striatum is relevant to the higher control of storage in micturition function in PD.

Synthesis and Biological Evaluation of [18F]FECNT-d4 as a Novel PET Agent for Dopamine Transporter Imaging.

PURPOSE: The dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson's disease (PD) and other diseases with nigrostriatal degeneration. 2ß-Carbomethoxy-3ß-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo. PROCEDURES: The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC. RESULTS: [18F]FECNT-d4 was synthesized at an average activity yield of 46 ± 17 % (n = 15) and the molar activity was 67 ± 12 GBq/µmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT. CONCLUSION: The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders.