Fluorescence-tagged salivary small extracellular vesicles as a nanotool in early diagnosis of Parkinson's disease.

BACKGROUND: Parkinson's disease is generally asymptomatic at earlier stages. At an early stage, there is an extensive progression in the neuropathological hallmarks, although, at this stage, diagnosis is not possible with currently available diagnostic methods. Therefore, the pressing need is for susceptibility risk biomarkers that can aid in better diagnosis and therapeutics as well can objectively serve to measure the endpoint of disease progression. The role of small extracellular vesicles (sEV) in the progression of neurodegenerative diseases could be potent in playing a revolutionary role in biomarker discovery. METHODS: In our study, the salivary sEV were efficiently isolated by chemical precipitation combined with ultrafiltration from subjects (PD = 70, healthy controls = 26, and prodromal PD = 08), followed by antibody-based validation with CD63, CD9, GAPDH, Flotillin-1, and L1CAM. Morphological characterization of the isolated sEV through transmission electron microscopy. The quantification of sEV was achieved by fluorescence (lipid-binding dye-labeled) nanoparticle tracking analysis and antibody-based (CD63 Alexa fluor 488 tagged sEV) nanoparticle tracking analysis. The total alpha-synuclein (α-synTotal) in salivary sEVs cargo was quantified by ELISA. The disease severity staging confirmation for n = 18 clinically diagnosed Parkinson's disease patients was done by 99mTc-TRODAT-single-photon emission computed tomography. RESULTS: We observed a significant increase in total sEVs concentration in PD patients than in the healthy control (HC), where fluorescence lipid-binding dye-tagged sEV were observed to be higher in PD (p = 0.0001) than in the HC using NTA with a sensitivity of 94.34%. In the prodromal PD cases, the fluorescence lipid-binding dye-tagged sEV concentration was found to be higher (p = 0.008) than in HC. This result was validated through anti-CD63 tagged sEV (p = 0.0006) with similar sensitivity of 94.12%. We further validated our findings with the ELISA based on α-synTotal concentration in sEV, where it was observed to be higher in PD (p = 0.004) with a sensitivity of 88.24%. The caudate binding ratios in 99mTc-TRODAT-SPECT represent a positive correlation with sEV concentration (r = 0.8117 with p = 0.0112). CONCLUSIONS: In this study, for the first time, we have found that the fluorescence-tagged sEV has the potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD.

Neuroimaging of Dopamine Transporter Density in the Striatum of Disordered Gamblers.

The aim of the present research was to add to the growing literature on dopamine and gambling disorder (GD) by assessing whether GD is associated with dopamine transporter (DAT) density in the ventral striatum compared to healthy controls and whether DAT density was associated with key characteristics of GD (e.g., abstinence, craving). In a cross-sectional investigation using single-photon emission computed tomography with a technetium-99m-labeled tropane derivative as a radiotracer with SPECT imaging, fifteen participants with GD and 15 controls (non-gambling individuals, matched for age, gender, handedness, and smoking status) were measured. The GD group completed self-reported questionnaires regarding gambling. Striatal DAT density did not differ between the two groups. Conversely, striatal DAT density correlated significantly with various measures of recent gambling, but not with measures of chronic gambling. Multivariate analysis, adjusted for age and smoking status, showed that DAT density in the left striatum correlated positively with time spent gambling and gambling craving in the last month, whereas DAT density in the right striatum correlated negatively with abstinence self-efficacy. The results suggests that DAT density in the striatum is associated with recent gambling activity and gambling expectation.

The Titrated Mannitol Improved Central [99mTc] Tc TRODAT-1 Uptake in an Animal Model-A Clinically Feasible Application.

[99mTc]Tc TRODAT-1 is a widely used single photon emission tomography (SPECT) radiopharmaceutical in Asian practice for early detection of central dopaminergic disorders. However, its imaging quality remains sub-optimal. To overcome this problem, mannitol, an osmotic agent was used to observe its effect on improving striatal [99mTc]Tc TRODAT-1 uptake in rat brain by titrated human dosages to investigate a clinically feasible way to improve human imaging quality. [99mTc]Tc TRODAT-1 synthesis and quality control were performed as described. Sprague-Dawley rats were used for this study. The animal in vivo nanoSPECT/CT and ex vivo autoradiography were employed to observe and verify the striatal [99mTc]Tc TRODAT-1 uptake in rat brains using clinically equivalent doses (i.e., 0, 1 and 2 mL groups, each n = 5) of mannitol (20% w/v, equivalent to 200 mg/mL) by an intravenous administration. Specific binding ratios (SBRs) were calculated to express the central striatal uptake in different experimental groups. In the NanoSPECT/CT imaging, the highest SBRs of striatal [99mTc]Tc TRODAT-1 were reached at 75-90 min post-injection. The averaged striatal SBRs were 0.85 ± 0.13 (2 mL normal saline, the control group), 0.94 ± 0.26 (1 mL mannitol group) and 1.36 ± 0.12 (2 mL mannitol group, p < 0.01 which were significantly different than the control as well as 1 mL mannitol groups (p < 0.05). The SBRs from ex vivo autoradiography also showed a comparable trend of the striatal [99mTc]Tc TRODAT-1 uptake in the 2 mL, 1 mL mannitol and the control groups (1.76 ± 0.52, 0.91 ± 0.29, and 0.21 ± 0.03, respectively, p < 0.05). No remarkable changes of vital signs were found in the mannitol groups and the controls. Pre-treated mannitol revealed a significant increase of the central striatal [99mTc]Tc TRODAT-1 uptake in a rat model which not only enabled us to perform pre-clinical studies of dopaminergic related disorders but also provided a potential way to further optimize image quality in clinical practice.

Experimental evaluation of absolute quantification in 99m Tc-TRODAT-1 SPECT/CT brain dopamine transporter (DAT) studies.

OBJECTIVE: To evaluate the quantitative accuracy of clinical brain dopamine transporters (DAT) investigations utilizing 99m Tc-TRODAT-1 single-photon emission computed tomography (SPECT)/computed tomography (CT) in experimental and clinical settings. MATERIALS AND METHODS: The study used an experimental phantom evaluation and a clinical dataset. Three-dimensional-ordered subsets expectation-maximization reconstructed the original and resampled datasets using attenuation correction, scatter correction, and resolution recovery. The reconstructed data were analyzed and reported as percentage difference, standardized uptake value reference (SUVr), and a coefficient of variation (CoV). The Taguchi method tested the impact of the three different parameters on signal-to-noise ratio (SNR) and SUVr, including number iteration, Poisson resampling, and phantom setup, with and without the plaster of Paris (POP). Six 99m Tc-TRODAT-1 SPECT/CT scans were acquired in healthy subjects for verification purposes. RESULTS: The percentage activity difference between the phantom with and without POP is 20% and 5%, respectively. The SUVr reveals a 10% underestimate for both with and without POP. When it comes to the influence of Poisson resampling, the SUVr value for 75% Poisson resampling indicates 10% underestimation on both sides of the caudate and putamen area, with and without POP. When 25% of Poisson resampling is applied, the SUVr value is overestimated (±35%). In the Taguchi analysis, iteration numbers were the most dominant factor with the F-value of 9.41 and the contribution rate of 52.66% (p < 0.05) for SNR. In comparison, F-value of 9.1 for Poisson resampled with contribution rate of 58.91% (p < 0.05) for SUVr. Reducing counts by 25% from the original dataset resulted in a minimal bias in SUVr, compared to 50% and 75%. CONCLUSION: The optimal absolute SPECT/CT quantification of brain DAT studies using 99m Tc-TRODAT-1 appears achievable with at least 4i10s and SUVr as the surrogate parameter. In clinical investigations, it is possible to reduce the recommended administered dose by up to 25% while maintaining accurate measurement.

Feasible Classified Models for Parkinson Disease from 99mTc-TRODAT-1 SPECT Imaging.

The neuroimaging techniques such as dopaminergic imaging using Single Photon Emission Computed Tomography (SPECT) with 99mTc-TRODAT-1 have been employed to detect the stages of Parkinson's disease (PD). In this retrospective study, a total of 202 99mTc-TRODAT-1 SPECT imaging were collected. All of the PD patient cases were separated into mild (HYS Stage 1 to Stage 3) and severe (HYS Stage 4 and Stage 5) PD, according to the Hoehn and Yahr Scale (HYS) standard. A three-dimensional method was used to estimate six features of activity distribution and striatal activity volume in the images. These features were skewness, kurtosis, Cyhelsky's skewness coefficient, Pearson's median skewness, dopamine transporter activity volume, and dopamine transporter activity maximum. Finally, the data were modeled using logistic regression (LR) and support vector machine (SVM) for PD classification. The results showed that SVM classifier method produced a higher accuracy than LR. The sensitivity, specificity, PPV, NPV, accuracy, and AUC with SVM method were 0.82, 1.00, 0.84, 0.67, 0.83, and 0.85, respectively. Additionally, the Kappa value was shown to reach 0.68. This claimed that the SVM-based model could provide further reference for PD stage classification in medical diagnosis. In the future, more healthy cases will be expected to clarify the false positive rate in this classification model.

Clinical utility of (99m Tc)-TRODAT-1 scans to differentiate Parkinsonian syndromes: case studies and commentary.

The differential diagnosis of Parkinsonian syndromes is challenging, especially in the elderly as they often have complex presentations. Nuclear imaging modalities can increase diagnostic accuracy. Single-photon emission tomography (SPECT) using the ligand (99m Tc)-TRODAT-1 is used overseas but is yet to be approved in Australia. Three pilot cases of clinically unclear Parkinsonian syndromes from the Royal North Shore Hospital Aged Care Department who underwent (99m Tc)-TRODAT-1 scans are described. From experience overseas, the (99m Tc)-TRODAT-1 scan has clinical utility in the differential diagnosis of Parkinsonian syndromes. (99m Tc)-TRODAT-1 has a lower cost and greater availability than other ligands. Our initial scan findings are largely consistent with the clinical picture, but low specific binding can affect scan interpretation. (99m Tc)-TRODAT-1 is a potential tool in the differential diagnosis of Parkinsonian syndromes. Further experience regarding its effect on patient outcomes and cost effectiveness is required before routine clinical use can be recommended.

Neuroimaging in Parkinsonian Disorders.

Neuroimaging (NI) in Parkinson's disease (PD) includes functional techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT), and morphological imaging using magnetic resonance imaging (MRI) and transcranial sonography to probe different aspects of the neurobiology of PD. Changes in neurotransmitters in various regions of the brain and their influence on brain networks is the basis for the motor symptoms of PD which are interrogated by NI. The recent Movement Disorders Society Clinical Diagnostic Criteria for PD (MDS-PD) have included the results of a few of these neuroimaging techniques to serve as single supportive criteria or absolute exclusion criteria for the diagnosis of PD. While dopaminergic imaging is useful in the early stages of disease to differentiate the neurodegenerative versus non-degenerative causes of parkinsonism like essential tremors, it has also been used for the differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer's disease (AD), for inclusion of PD patients into clinical trials and for evaluating response to cell-replacement therapies in PD. Metabolic patterns on F-18 fluorodeoxyglucose positron emission tomography have been used effectively for the classification and differential diagnosis of the parkinsonian syndromes using visual and quantitative approaches. Disease related network-patterns have been used for a completely automated approach to differential diagnosis of parkinsonian syndromes on a single case basis. Structural MRI and advanced MR techniques have been used for the classification of PD and the atypical parkinsonian syndromes. Thus, multimodal imaging in PD may aid in an early, accurate and objective diagnostic classification by highlighting the underlying neurochemical and neuroanatomical changes that underlie this spectrum of disorders. The present challenge in PD is to develop radioligands which could bind selectively to alphasynuclein in-vivo.

Highlights of articles published in annals of nuclear medicine 2016.

This article is the first installment of highlights of selected articles published during 2016 in the Annals of Nuclear Medicine, an official peer-reviewed journal of the Japanese Society of Nuclear Medicine. A companion article highlighting selected articles published during 2016 in the European Journal of Nuclear Medicine and Molecular Imaging, which is the official peer-reviewed journal of the European Association of Nuclear Medicine, will also appear in the Annals Nuclear Medicine. This new initiative by the respective journals will continue as an annual endeavor and is anticipated to not only enhance the scientific collaboration between Europe and Japan but also facilitate global partnership in the field of nuclear medicine and molecular imaging.

Standardization and Clinical Use of a Single-vial Formulation of Technetium-99m-Trodat Using Autoclave Method.

Background: Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra. SPECT imaging using technetium-99m [99mTc] labeled trodat is the choice of imaging to differentiate PD from its other forms like drug-induced PD. Aims and Objectives: The main objective of our study was to prepare in-house sterile formulation of [99mTc]Tc-trodat and use in clinics. Materials and Methods: The labeling of trodat was standardized using glucoheptonate sodium salt (GHA), stannous chloride dihydrate (in 0.05 N HCl), and ethylenediaminetetraacetic acid (Na-EDTA). The preparation was mixed and autoclaved at 15 psi for 15 min. The standardised formulation was stored at 4°C, -20°C and -80°C and labeling with 99mTc was tested for up to 6 days. The radiochemical purity, chemical impurities, and endotoxin levels were tested. The frozen formulation was tested in swiss mice (n = 3) for biodistribution studies at 4 h. Around 18 ± 2 mCi was injected intravenously in each patient (n = 5) and the image was acquired at 4 h post-injection. Results: The radiochemical purity of the preparation was 98.3 ± 1.4% with a retention time of 16.8 ± 1.5 min as compared to 4.0 ± 0.5 min for free 99mTc. Animal distribution showed highest uptake in liver and dual excretion via hepatobiliary and renal system. [99mTc]Tc-trodat imaging was able to differentiate both caudate and putamen. Conclusions: In-house frozen preparation was advantageous, as it has decreased the chance of manual error as compared to daily make up formulations and economical as compared to commercially available kits.

Connecting the Dots: Exploring the Relationship between Optical Coherence Tomography and 99mTc-TRODAT-1 SPECT Parameters in Parkinson's Disease.

Background and Objective: While optical coherence tomography (OCT) is explored as a potential biomarker in Parkinson's disease (PD), technetium-99m-labeled tropane derivative (99mTc-TRODAT-1) single-photon emission computed tomography (SPECT) imaging has a proven role in diagnosing PD. Our objective was to compare the OCT parameters in PD patients and healthy controls (HCs) and correlate them with 99mTc-TRODAT-1 parameters in PD patients. Materials and Methods: This cross-sectional study included 30 PD patients and 30 age- and gender-matched HCs. Demographic data, PD details including Movement Disorders Society Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III) and Hoehn-Yahr (HY) staging, and OCT parameters including macular and peripapillary retinal nerve fiber layer (RNFL) thickness in bilateral eyes were recorded. PD patients underwent 99mTc-TRODAT-1 SPECT imaging. The terms "ipsilateral" and "contralateral" were used with reference to more severely affected body side in PD patients and compared with corresponding sides in HCs. Results: PD patients showed significant ipsilateral superior parafoveal quadrant (mean ± standard deviation [SD] = 311.10 ± 15.90 vs. 297.57 ± 26.55, P = 0.02) and contralateral average perifoveal (mean ± SD = 278.75 ± 18.97 vs. 269.08 ± 16.91, P = 0.04) thinning compared to HCs. Peripapillary RNFL parameters were comparable between PD patients and HCs. MDS-UPDRS-III score and HY stage were inversely correlated to both ipsilateral (Spearman rho = -0.52, P = 0.003; Spearman rho = -0.47, P = 0.008) and contralateral (Spearman rho = -0.53, P = 0.002; Spearman rho = -0.58, P < 0.001) macular volumes, respectively. PD duration was inversely correlated with ipsilateral temporal parafoveal thickness (ρ = -0.41, P = 0.02). No correlation was observed between OCT and 99mTc-TRODAT-1 SPECT parameters in PD patients. Conclusion: Compared to HCs, a significant thinning was observed in the ipsilateral superior parafoveal quadrant and the contralateral average perifoveal region in PD patients. Macular volume and ipsilateral temporal parafoveal thickness were inversely correlated with disease severity and duration, respectively. OCT and 99mTc-TRODAT-1 SPECT parameters failed to correlate in PD patients.

Does TRODAT-1 SPECT Uptake Correlate with Cerebrospinal Fluid α-Synuclein Levels in Mid-Stage Parkinson's Disease?

BACKGROUND: Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons with impaired motor and non-motor symptoms. It has been suggested that motor asymmetry could be caused due to an imbalance in dopamine levels, as visualized by dopamine transporter single emission computed tomography test (DAT-SPECT), which might be related to indirect measures of neurodegeneration, evaluated by the Montreal Cognitive Assessment (MOCA) and α-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and α-synuclein levels in PD. METHODS: A total of 28 patients in the moderate-advanced stage of PD were subjected to neurological evaluation, TRODAT-1-SPECT/CT imaging, MOCA, and quantification of the levels of α-synuclein. RESULTS: We found that α-synuclein in the CSF was correlated with global cognition (positive correlation, r2 = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r2 = 0.4, p = 0.005), and striatum (positive correlation, r2 = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF α-synuclein, and cognition, thus suggesting that they may be lost with disease progression. CONCLUSIONS: Our data highlight the importance of understanding the dysfunction of the dopaminergic system in the basal ganglia and its complex interactions in modulating cognition.

99m-Tc TRODAT Single-Photon Emission Computerized Tomography Scan Image Compression using Singular Value Decomposition.

Introduction: The objective of the study was to compress 99m-Tc TRODAT single-photon emission computerized tomography (SPECT) scan image using Singular Value Decomposition (SVD) into an acceptable compressed image and then calculate the compression factor. Materials and Methods: The SVD of every image from the image dataset of 2256 images (of forty-eight 99m-Tc TRODAT SPECT studies [48 studies X 47 trans-axial images = 2256 trans-axial images]) was computed and after truncating singular values smaller than a threshold, the compressed image was reconstructed. The SVD computation time and percentage compression achieved were calculated for each image. Two nuclear medicine physicians visually compared compressed image with its original image, and labeled it as either acceptable or unacceptable. Compressed image having loss of clinical details or presence of compression artifact was labeled unacceptable. The quality of compressed image was also assessed objectively using the following image quality metrics: Error, structural similarity (SSIM), brightness, global contrast factor (GCF), contrast per pixel (CPP), and blur. We also compared the TRODAT uptake in basal ganglia estimated from the compressed image and original image. Results: Nuclear Medicine Physician labeled each image acceptable, as they found compressed image identical to its original image. The values of brightness, GCF, CPP, and blur metrics show that compressed images are less noisy, brighter, and sharper than its original image. The median values of error (0.0006) and SSIM (0.93) indicate that the compressed images were approximately identical to its original image. In 39 out of 48 studies, the percentage difference in TRODAT uptake (in basal ganglia from compressed and original image) was negligible (approximately equal to zero). In remaining 9 studies, the maximum percentage difference was 13%. The SVD computation time and percentage compression achieved for a TRODAT study were 0.17398 s and up to 54.61%, respectively. Conclusions: The compression factor up to 54.61% was achieved during 99m-Tc TRODAT SPECT scan image compression using SVD, for an acceptable compressed image.

A Pilot Study of the Striatal Dopamine Transporter Levels in Kratom-Dependent and Normal Subjects Using 99mTc-TRODAT-1 Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT).

OBJECTIVE: The study aims to elucidate the effects of kratom addiction on dopamine transporter (DAT) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N20,S2,S20]oxo-[1R-(exo-exo)]-[99mTc] technetium (99mTc-TRODAT-1) brain single photon emission computed tomography-computed tomography (SPECT-CT) in kratom-dependent and healthy subjects. MATERIALS AND METHODS: We recruited 12 kratom-dependent subjects and 13 healthy men to participate in this study. Addiction, craving, depression, and cognitive scores were assessed. All subjects received a single bolus injection of 99mTc-TRODAT-1 with 914.1 MBq ± 65.5 of activity (mean ± SD). The brain SPECT-CT images were reconstructed using 3D ordered subset expectation maximization (3D-OSEM) along with attenuation correction (AC), scatter correction (SC), and resolution recovery (RR) with an iteration number of four and a subset of 10. The Cohen's Kappa interrater-reliability between two raters, the standardized uptake value of body weight (SUVBW), and the asymmetrical index percentage (AI%) were evaluated. RESULTS: Kappa statistics showed a fine agreement of abnormal 99mTc-TRODAT-1 uptake in the striatum region for the kratom-dependent group with the κ value of 0.69 (p = 0.0001), and the percentage of agreement for rater 1 and rater 2 was 56% and 64%, respectively. There was a reduction in average SUV in kratom-dependent subjects compared to healthy control subjects in the left caudate and left striatum (0.938 vs. 1.251, p = 0.014, and 1.055 vs. 1.29, p = 0.036, respectively). There was a significant difference in the AI% of the caudate region between the kratom-dependent group and the normal group (33% vs. 14%, p = 0.019). CONCLUSION: Our findings signify that kratom addiction, may cause a change in DAT level and the results can be confirmed using 99mTc-TRODAT-1 SPECT-CT.

Generative adversarial network-based attenuation correction for 99mTc-TRODAT-1 brain SPECT.

Background: Attenuation correction (AC) is an important correction method to improve the quantification accuracy of dopamine transporter (DAT) single photon emission computed tomography (SPECT). Chang's method was developed for AC (Chang-AC) when CT-based AC was not available, assuming uniform attenuation coefficients inside the body contour. This study aims to evaluate Chang-AC and different deep learning (DL)-based AC approaches on 99mTc-TRODAT-1 brain SPECT using clinical patient data on two different scanners. Methods: Two hundred and sixty patients who underwent 99mTc-TRODAT-1 SPECT/CT scans from two different scanners (scanner A and scanner B) were retrospectively recruited. The ordered-subset expectation-maximization (OS-EM) method reconstructed 120 projections with dual-energy scatter correction, with or without CT-AC. We implemented a 3D conditional generative adversarial network (cGAN) for the indirect deep learning-based attenuation correction (DL-ACµ) and direct deep learning-based attenuation correction (DL-AC) methods, estimating attenuation maps (µ-maps) and attenuation-corrected SPECT images from non-attenuation-corrected (NAC) SPECT, respectively. We further applied cross-scanner training (cross-scanner indirect deep learning-based attenuation correction [cull-ACµ] and cross-scanner direct deep learning-based attenuation correction [call-AC]) and merged the datasets from two scanners for ensemble training (ensemble indirect deep learning-based attenuation correction [eDL-ACµ] and ensemble direct deep learning-based attenuation correction [eDL-AC]). The estimated µ-maps from (c/e)DL-ACµ were then used in reconstruction for AC purposes. Chang's method was also implemented for comparison. Normalized mean square error (NMSE), structural similarity index (SSIM), specific uptake ratio (SUR), and asymmetry index (%ASI) of the striatum were calculated for different AC methods. Results: The NMSE for Chang's method, DL-ACµ, DL-AC, cDL-ACµ, cDL-AC, eDL-ACµ, and eDL-AC is 0.0406 ± 0.0445, 0.0059 ± 0.0035, 0.0099 ± 0.0066, 0.0253 ± 0.0102, 0.0369 ± 0.0124, 0.0098 ± 0.0035, and 0.0162 ± 0.0118 for scanner A and 0.0579 ± 0.0146, 0.0055 ± 0.0034, 0.0063 ± 0.0028, 0.0235 ± 0.0085, 0.0349 ± 0.0086, 0.0115 ± 0.0062, and 0.0117 ± 0.0038 for scanner B, respectively. The SUR and %ASI results for DL-ACµ are closer to CT-AC, Followed by DL-AC, eDL-ACµ, cDL-ACµ, cDL-AC, eDL-AC, Chang's method, and NAC. Conclusion: All DL-based AC methods are superior to Chang-AC. DL-ACµ is superior to DL-AC. Scanner-specific training is superior to cross-scanner and ensemble training. DL-based AC methods are feasible and robust for 99mTc-TRODAT-1 brain SPECT.

Cortical excitability in patients with REM sleep behavior disorder with abnormal TRODAT-1 SPECT scan: an insight into prodromal Parkinson's disease.

Introduction: REM Sleep Behavior Disorder (RBD) has been highlighted to identify a patient with prodromal Parkinson's disease (PD). Although many studies focus on biomarkers to predict an RBD patient's evolution from prodromal PD to clinical PD, the neurophysiological perturbation of cortical excitability has not yet been well elucidated. Moreover, no study describes the difference between RBD with and without abnormal TRODAT-1 SPECT. Methods: By measuring the amplitude of motor evoked potentials (MEP), the cortical excitability changes after transcranial magnetic stimulation (TMS) were evaluated in 14 patients with RBD and eight healthy controls (HC). Seven of the 14 patients with RBD showed abnormal TRODAT-1 (TRA-RBD), and seven were normal (TRN-RBD). The tested parameters of cortical excitability include resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), contralateral silence period (CSP), and input-output recruitment curve. Results: The RMT and AMT showed no difference among the three studied groups. There was only SICI at inter-stimuli-interval 3 ms revealing group differences. The TRA-RBD demonstrated significant differences to HC in these aspects: decreased SICI, increased ICF, shortening of CSP, and augmented MEP amplitude at 100% RMT. Moreover, the TRA-RBD had a smaller MEP facilitation ratio at 50% and 100% of maximal voluntary contraction when compared to TRN-RBD. The TRN-RBD did not present any difference to HC. Conclusion: We showed that TRA-RBD shared similar cortical excitability changes with clinical PD. These findings would provide further insight into the concept that RBD is the highly prevalent entity in prodromal PD.

Calix[n]arene-based immunogens: A new non-proteic strategy for anti-cocaine vaccine.

Introduction: Cocaine use disorder is a significant public health issue without a current specific approved treatment. Among different approaches to this disorder, it is possible to highlight a promising immunologic strategy in which an immunogenic agent may reduce the reinforcing effects of the drug if they are able to yield sufficient specific antibodies capable to bind cocaine and/or its psychoactive metabolites before entering into the brain. Several carriers have been investigated in the anti-cocaine vaccine development; however, they generally present a very complex chemical structure, which potentially hampers the proper assessment of the coupling efficiency between the hapten units and the protein structure. Objectives: The present study reports the design, synthesis and preclinical evaluation of two novel calix[n]arene-based anti-cocaine immunogens (herein named as V4N2 and V8N2) by the tethering of the hydrolysis-tolerant hapten GNE (15) on calix[4]arene and calix[8]arene moieties. Methods: The preclinical assessment corresponded to the immunogenicity and dose-response evaluation of V4N2 and V8N2. The potential of the produced antibodies to reduce the passage of cocaine analogue through the blood-brain-barrier (BBB), modifying its biodistribution was also investigated. Results: Both calix[n]arene-based immunogens elicited high titers of cocaine antibodies that modified the biodistribution of a cocaine radiolabeled analogue (99mTc-TRODAT-1) and decreased cocaine-induced behavior, according to an animal model. Conclusion: The present results demonstrate the potential of V4N2 and V8N2 as immunogens for the treatment of cocaine use disorder.

Lewy Body Dementia Associated with Anti-IgLON 5 Encephalitis Detected on 18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and 99mTc-TRODAT Single-Photon Emission Computed Tomography/Computed Tomography.

We present a case of Anti-IgLON 5 encephalitis with Lewy body dementia. 18F fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan and 99 mTc-TRODAT-1 SPECT/CT scan were done. 99 mTc-TRODAT-1 scan findings revealed severely reduced concentration of dopamine transporter in bilateral basal ganglia, suggestive of a degenerative parkinsonian disorder. 18F-FDG PET scan findings were suggestive of moderate-to-severe hypometabolism in the bilateral parieto-temporal and bilateral occipital cortices including the primary visual cortices, supporting Lewy body spectrum disease with associated hypermetabolism in the bilateral sensorimotor cortices, bilateral basal ganglia, thalami, brain stem, and bilateral cerebellar hemispheres suggestive of inflammatory pathology.

18F-FDG PET/CT and 99mTc-TRODAT Scan Findings in the Variants of Progressive Supranuclear Palsy and Correlation With Clinical Findings.

Aim: The aim of this study is to elucidate the patterns of characteristic hypometabolism on 18F-Fluoro Deoxy-glucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in the variants of Progressive supranuclear palsy (PSP) and its correlation with their core clinical features. Material and Methods: A retrospective analysis of 88 subjects with clinically suspected PSP was done. An institutional informed consent to participate in the study was taken from all the subjects. All the subjects had undergone a prior 99mTechnetium labeled Tropane derivative of dopamine transporter Single Photon Emission Computed Tomography (99mTc TRODAT-1 SPECT) study and had abnormal scans to confirm degenerative parkinsonism. The subjects were clinically examined by the neurologists using the Progressive Supranuclear Palsy Rating Scale proposed by the Movement Disorder Society and were further clinically segregated into eight subtypes. All the included subjects further underwent a detailed clinical analysis to obtain their individual Schwab and England activities of daily living scale and Modified Hoehn and Yahr staging by a neurologist. All the subjects underwent 18F-FDG PET/CT scan after adequate preparation. The scans were analyzed both qualitatively (visually) and quantitatively using Statistical Parametric Mapping. Results: The frontal, limbic, and sensorimotor cortices represented the common areas of hypometabolism among all the subtypes of PSP. The subcortical regions showing the most significant hypometabolism were the thalami, mid-brain, nucleus accumbens, caudate, globus pallidus, and putamen in descending order. Multiple cortical and subcortical regions of hypometabolism were identified in different subtypes of PSP. Conclusion: The characteristic patterns of hypometabolism observed in the different subgroups were more apparent on quantification and based on visual analysis alone, it may not be possible to differentiate the different subtypes of PSP. A good correlation was seen between some of the core clinical features and hypometabolic clusters.

Real-World Testing of a Machine Learning-Derived Visual Scale for Tc99m TRODAT-1 for Diagnosing Lewy Body Disease: Comparison with a Traditional Approach Using Semiquantification.

Objectives: Abnormal dopamine transporter (DAT) uptake is an important biomarker for diagnosing Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We evaluated a machine learning-derived visual scale (ML-VS) for Tc99m TRODAT-1 from one center and compared it with the striatal/background ratio (SBR) using semiquantification for diagnosing LBD in two other centers. Patients and Methods: This was a retrospective analysis of data from a history-based computerized dementia diagnostic system. MT-VS and SBR among normal controls (NCs) and patients with PD, PD with dementia (PDD), DLB, or Alzheimer's disease (AD) were compared. Results: We included 715 individuals, including 122 NCs, 286 patients with PD, 40 with AD, 179 with DLB, and 88 with PDD. Compared with NCs, patients with PD exhibited a significantly higher prevalence of abnormal DAT uptake using all methods. Compared with the AD group, PDD and DLB groups exhibited a significantly higher prevalence of abnormal DAT uptake using all methods. The distribution of ML-VS was significantly different between PD and NC, DLB and AD, and PDD and AD groups (all p < 0.001). The correlation coefficient of ML-VS/SBR in all participants was 0.679. Conclusions: The ML-VS designed in one center is useful for differentiating PD from NC, DLB from AD, and PDD from AD in other centers. Its correlation with traditional approaches using different scanning machines is also acceptable. Future studies should develop models using data pools from multiple centers for increasing diagnostic accuracy.

Multi-Modal Synergistic 99mTc-TRODAT-1 SPECT and MRI for Evaluation of the Efficacy of Hyperbaric Oxygen Therapy in CO-Induced Delayed Parkinsonian and Non-Parkinsonian Syndromes.

Background: Delayed neuropsychiatric syndrome (DNS) is characterized by motor dysfunction after acute carbon monoxide (CO) poisoning. We examined the relationship between dopamine transporter (DAT) loss using kit-based Tc-99m-TRODAT-1 (DAT single-photon emission-computed tomography (SPECT) radioligand) and globus pallidus necrosis on MRI, DAT availability before and after hyperbaric oxygen therapy (HBOT), and feasibility of Tc-99m-TRODAT-1 as an index for parkinsonian syndrome in CO poisoning. Methods: Twenty-one CO-intoxicated patients (mean ± SD age, 38.6 ± 11.4; range, 20−68 years) with DNS underwent Tc-99m-TRODAT-1 SPECT and MRI before HBOT and follow-up Tc-99m-TRODAT-1 SPECT to assess DAT recovery. Neurological examinations for Parkinsonism were performed after development of DNS. Results: Over 70% (15/21) of DNS patients showed globus pallidus necrosis on MRI. Significantly lower bilateral striatal DAT availability was associated with globus pallidus necrosis (p < 0.005). Moreover, 68.4% (13/19) of DNS subjects with Parkinsonian syndrome had lower bilateral striatal DAT availability vs. non-parkinsonian subjects pre- or post-HBOT. The SURs for both striata increased by ~11% post-HBOT in the Parkinsonian group; however, the left striatum presented a significantly higher DAT recovery rate than the right (*** p < 0.005). Conclusions: Coupled Tc-99m TRODAT-1 SPECT and MRI could assist evaluation of Parkinsonism risk and indicate DAT availability after HBOT in CO-poisoned patients with DNS.