Specific Uptake Ratio Research Articles

Parkinson's disease and levodopa-induced dyskinesias: a quantitative analysis through 99mTc-TRODAT-1 SPECT imaging of the brain.

To compare the dopamine transporter (DAT) density with other risk factors for L-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD), with and without LID. We evaluated 67 subjects: 44 patients with idiopathic PD of varying degrees of severity (PD group), and 23 healthy age-matched volunteers (control group). Among the 44 patients in the PD group, 29 were male and the following means were recorded at baseline: age, 59 ± 7 years; disease duration, 10 ± 6 years; Hoehn and Yahr (H&Y) stage, 2.16 ± 0.65; and Unified Parkinson's Disease Rating Scale part III (UPDRS III) score, 29.74 ± 17.79. All subjects underwent 99mTc-TRODAT-1 SPECT. We also calculated specific uptake ratios or binding potentials in the striatum. The DAT density in the ipsilateral and contralateral striata was lower in the PD group. The variables disease duration, L-DOPA dosage, doses per day, L-DOPA effect duration time, H&Y stage, and UPDRS III score explained the occurrence of LID. The DAT density in the ipsilateral striatum, contralateral striatum, and caudate nucleus was lower in the patients with LID than in those without. Our findings suggest that presynaptic dopaminergic denervation is associated with LID in individuals with PD.

Monoaminergic Degeneration and Ocular Motor Abnormalities in De Novo Parkinson's Disease.

Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. Drug-naive PD patients who underwent N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography scans and video-oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. One-hundred twenty-four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS-UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey-Complex-Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin-predominant region, but did not correlate with parkinsonism severity scores. Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society.

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

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. 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. 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. 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.

Comparison of 18 F-DOPA and 18 F-DTBZ for PET/CT Imaging of Idiopathic Parkinson Disease.

The aim of this study was to compare 2 imaging tracers, 18 F-DOPA and 18 F-DTBZ, for PET/CT imaging in idiopathic Parkinson disease (PD). We recruited 32 PD patients and 12 healthy controls in this study. All subjects underwent both 18 F-DOPA and 18 F-DTBZ PET/CT, and the results were interpreted by visual analysis and semiquantitative analysis (specific uptake ratios [SURs]). A 1-way analysis of variance was used to compare the clinical data and the SURs among the patients at different stages. Regression analysis was performed to analyze the correlation between the SURs and the clinical data. Among the PD patients, there were 7 patients in Hoehn and Yahr stage I, 14 patients in stage II, and 11 patients in stage III. Linear correlation was found in striatal SURs between the 2 tracers ( P < 0.05). In patients of early stages, the striatal SUR decrease percent of 2 tracers had no statistical difference (paired t test, P > 0.05). By initial visual analysis, all the patients were interpreted as positive with 18 F-DBTZ (6 unilaterally, 26 bilaterally), and 31 cases were regarded as positive with 18 F-DOPA (8 unilaterally, 23 bilaterally). After setting the upper limit of SUR images with the putamen SURs of healthy controls (SUR T ), all patients were interpreted as positive with both tracers ( 18 F-DTBZ: 5 unilaterally, 27 bilaterally; 18 F-DOPA: 4 unilaterally, 28 bilaterally). 18 F-DTBZ and 18 F-DOPA could reflect the same level of dopaminergic neuron degeneration for PD in early stages, and they have the consistent visual analysis results.

Preliminary Results on the Long-Term Effects of Dextromethorphan on MDMA-Mediated Serotonergic Deficiency and Volumetric Changes in Primates Based on 4-[18F]-ADAM PET/MRI.

Alterations to the serotonergic system due to 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) consumption have been extensively documented. However, knowledge of the reversibility of these neurotoxic effects based on in vivo evaluations of serotonin transport (SERT) availability remains limited. This study aimed to evaluate the long-term neurotoxicity of MDMA after 66 months abstinence and explored whether Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor, could attenuate MDMA-induced neurotoxicity using 4-[18F]-ADAM, an imaging ligand that selectively targets SERT, with positron emission tomography technology (PET). Nine monkeys (Macaca cyclopis) were used in this study: control, MDMA, and DM + MDMA. Static 4-[18F]-ADAM PET was performed at 60 and 66 months after drug treatment. Serotonin transport (SERT) availability was presented as the specific uptake ratios (SURs) of 4-[18F]-ADAM in brain regions. Voxel-based region-specific SERT availability was calculated to generate 3D PET/MR images. Structural Magnetic Resonance Imaging (MRI) volumetric analysis was also conducted at 60 months. Significantly decreased 4-[18F]-ADAM SURs were observed in the striatum and thalamus of the MDMA group at 60 and 66 months compared to controls; the midbrain and frontal cortex SURs were similar at 60 and 66 months in the MDMA and control groups. All eleven brain regions showed significantly lower (∼13%) self-recovery rates over time; the occipital cortex and cingulate recovered to baseline by 66 months. DM attenuated MDMA-induced SERT deficiency on average, by ∼8 and ∼1% at 60 and 66 months, respectively; whereas significant differences were observed between the thalamus and amygdala of the MDMA and DM + MDMA groups at 66 months. Compared to controls, the MDMA group exhibited significantly increased (∼6.6%) gray matter volumes in the frontal cortex, occipital cortex, caudate nucleus, hippocampus, midbrain, and amygdala. Moreover, the gray matter volumes of the occipital cortex, hippocampus and amygdala correlated negatively with the 4-[18F]-ADAM SURs of the same regions. DM (n = 2) did not appear to affect MDMA-induced volumetric changes. The 4-[18F]-ADAM SURs, lower self-recovery rate and increased volumetric values indicate the occipital cortex, hippocampus and amygdala still exhibit MDMA-induced neurotoxicity after 66 months’ abstinence. Moreover, DM may prevent MDMA-induced serotonergic deficiency, as indicated by increased 4-[18F]-ADAM SURs and SERT availability, but not volumetric changes.

Pulsed Radiofrequency Upregulates Serotonin Transporters and Alleviates Neuropathic Pain-Induced Depression in a Spared Nerve Injury Rat Model.

Neuropathic pain (NP) is difficult to treat due to complex pathophysiological mechanisms. Pulsed radiofrequency (RRF) has been used widely with neuromodulation effect in refractory chronic pain treatment. A recent study found that PRF treatment may decrease chronic pain-related anxiety-depressant symptoms in patients, even though the mechanisms are unclear. Additionally, accumulated evidence has shown serotonin uptake is correlated with various neuropsychiatric diseases. Therefore, we investigated the effects and underlying mechanisms of PRF on depression-like behaviors, resulting from spared nerve injury (SNI)-induced NP. We examined the indexes of mechanical allodynia, cold allodynia, depression-like behavior, and blood cytokines by dynamic plantar aesthesiometry, acetone spray test, forced swimming test, and ProcartaPlex multiplex immunoassays in male Wistar rats, respectively. Serotonin transporters (SERTs) in rat brains were examined by using 4-[18F]-ADAM/PET imaging. We found that specific uptake ratios (SURs) of SERTs were significantly decreased in the brain regions of the thalamus and striatum in rats with SNI-induced NP and depression-like behaviors. Additionally, the decrease in SERT density was correlated with the development of a depression-like behavior indicated by the forced swimming test results and pronounced IL-6 cytokines. Moreover, we demonstrated that PRF application could modulate the descending serotoninergic pathway to relieve pain and depression behaviors.

Co-registration Analysis of Fluorodopa and Fluorodeoxyglucose Positron Emission Tomography for Differentiating Multiple System Atrophy Parkinsonism Type From Parkinson's Disease.

It is difficult to differentiate between Parkinson's disease and multiple system atrophy parkinsonian subtype (MSA-P) because of the overlap of their signs and symptoms. Enormous efforts have been made to develop positron emission tomography (PET) imaging to differentiate these diseases. This study aimed to investigate the co-registration analysis of 18F-fluorodopa and 18F-flurodeoxyglucose PET images to visualize the difference between Parkinson's disease and MSA-P. We enrolled 29 Parkinson's disease patients, 28 MSA-P patients, and 10 healthy controls, who underwent both 18F-fluorodopa and 18F-flurodeoxyglucose PET scans. Patients with Parkinson's disease and MSA-P exhibited reduced bilateral striatal 18F-fluorodopa uptake (p < 0.05, vs. healthy controls). Both regional specific uptake ratio analysis and statistical parametric mapping analysis of 18F-flurodeoxyglucose PET revealed hypometabolism in the bilateral putamen of MSA-P patients and hypermetabolism in the bilateral putamen of Parkinson's disease patients. There was a significant positive correlation between 18F-flurodeoxyglucose uptake and 18F-fluorodopa uptake in the contralateral posterior putamen of MSA-P patients (rs = 0.558, p = 0.002). Both 18F-flurodeoxyglucose and 18F-fluorodopa PET images showed that the striatum was rabbit-shaped in the healthy control group segmentation analysis. A defective rabbit-shaped striatum was observed in the 18F-fluorodopa PET image of patients with Parkinson's disease and MSA-P. In the segmentation analysis of 18F-flurodeoxyglucose PET image, an intact rabbit-shaped striatum was observed in Parkinson's disease patients, whereas a defective rabbit-shaped striatum was observed in MSA-P patients. These findings suggest that there were significant differences in the co-registration analysis of 18F-flurodeoxyglucose and 18F-fluorodopa PET images, which could be used in the individual analysis to differentiate Parkinson's disease from MSA-P.

The High Affinity Dopamine D2 Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders.

The dopamine D2 receptor exists in two different states, D2high and D2low; the former is the functional form of the D2 receptor and associates with intracellular G-proteins. The D2 agonist [3H]MCL-536 has high affinity for the D2 receptor (Kd 0.8 nM) and potently displaces the binding of (R-(-)-N-n-propylnorapomorphine (NPA; Ki 0.16 nM) and raclopride (Ki 0.9 nM) in competition binding assays. Here, we further characterize [3H]MCL-536. [3H]MCL-536 was metabolically stable, with about 75% of the compound remaining intact after 1 h incubation with human liver microsomes. Blood-brain barrier penetration in rats was good, attaining at 15 min a % injected dose per gram of wet tissue (%ID/g) of 0.28 in males versus 0.42 in females in the striatum. Specific uptake ratios ([%ID/g striatum]/[%ID/g cerebellum]) were stable in males during the first 60 min and in females up to 15-30 min. The D2-rich striatum exhibited the highest uptake and slowest washout compared to D2-poor cortex or cerebellum. In peripheral organs, uptake peaked at 15 min but declined to baseline at 60 min, indicating good clearance from the body. In vitro autoradiography on transaxial and coronal brain sections showed specific binding of [3H]MCL-536, which was abolished by preincubation with D2/D3 ligands sulpiride, NPA, and raclopride and in the presence of the stable GTP analogue guanylylimidodiphosphate. In amphetamine-sensitized animals, striatal binding was higher than in controls, indicating specificity for the D2high receptor state. [3H]MCL-536's unique properties make it a valuable tool for research on neurological disorders involving the dopaminergic system like Parkinson's disease or schizophrenia.

Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer.

.Significance: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient.Aim: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall.Approach: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer’s specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram.Results: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties.Conclusions: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer’s specific uptake ratio.

Automatic Striatal ROI Delineation for Semi-quantitative Analysis of 99mTc-TRODAT-1 Brain SPECT Imaging

Single-photon emission computed tomography (SPECT) imaging, a relatively inexpensive nuclear imaging technique, has been used as a diagnostic tool for Parkinson’s disease (PD). The tracer 99mTc-TRODAT-1 is commonly used in Taiwan, where the imaging cost is covered under the national health insurance system. However, poor TRODAT-SPECT imaging resolution is a problem. Therefore, we developed a semi-quantitative program that can perform automatic region of interest (ROI) delineation for semi-quantifying striatal dopamine transporter activities. A total of 228 subjects were enrolled in this study, including PD patients (n = 62) and healthy controls (n = 166). The subjects received a 99mTc-TRODAT-1 brain SPECT scan. Some of the subjects (n = 40) also received a high-resolution magnetic resonance imaging (MRI) scan for the evaluation of the accuracy of the semi-quantitative assessment. In addition, the developed automatic ROI delineation method was used to calculate the striatal specific uptake ratio (SUR) in dopamine transporter imaging. The reproducibility of the SUR obtained using the method was compared to those in previous studies. Based on linear regression analysis (r2 = 0.92, correlation coefficient = 0.96), a correlation was found between the results obtained using the automatic ROI delineation method and those of the manual method in striatum with the corresponding MR images. The age-related decline of SUR availability measured in this study was 6.4% per decade. There was almost no difference between our results and those in related clinical studies. The proposed automatic ROI delineation program for SUR analysis was tested and used to estimate the ROIs in TRODAT-SPECT images to aid PD diagnosis. The program could be helpful for physicians who are inexperienced with TRODAT-SPECT images.

The Association Between Parkinson’s Disease and Attention-Deficit Hyperactivity Disorder

While Parkinson’s disease (PD) and attention-deficit hyperactivity disorder (ADHD) are two distinct conditions, it has been hypothesized that they share several overlapping anatomical and neurochemical changes. In order to investigate that hypothesis, this study used claims data from Taiwan’s Longitudinal Health Insurance Database 2000 to provide the significant nationwide population-based evidence of an increased risk of PD among ADHD patients, and the connection between the two conditions was not the result of other comorbidities. Moreover, this study showed that the patients with PD were 2.8 times more likely to have a prior ADHD diagnosis compared with those without a prior history of ADHD. Furthermore, an animal model of ADHD was generated by neonatally injecting rats with 6-hydroxydopamine (6-OHDA). These rats were subjected to behavior tests and the 99mTc-TRODAT-1 brain imaging at the juvenile stage. Compared to control group rats, the 6-OHDA rats showed a significantly reduced specific uptake ratio in the striatum, indicating an underlying PD-linked pathology in the brains of these ADHD phenotype-expressing rats. Overall, these results support that ADHD shares a number of anatomical and neurochemical changes with PD. As such, improved knowledge of the neurochemical mechanisms underlying ADHD could result in improved treatments for various debilitating neurological disorders, including PD.

Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline.

ObjectivesRapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near‐term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility‐weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits.MethodsSWI of the substantia nigra was performed in 46 RBD patients, 27 Parkinson’s patients, and 32 control subjects. Dorsal nigral hyperintensity (DNH) was scored by two blinded raters, and separately quantified using a semiautomated process. Forty‐two RBD patients were also imaged with 123I‐ioflupane single‐photon emission computed tomography (DaT SPECT/CT).ResultsConsensus visual DNH classification was possible in 87% of participants. 27.5% of RBD patients had lost DNH, compared with 7.7% of control subjects and 96% of Parkinson’s patients. RBD patients lacking DNH had significantly lower putamen dopaminergic SPECT/CT activity compared to RBD patients with DNH present (specific uptake ratios 1.89 vs. 2.33, P = 0.002). The mean quantified DNH signal intensity declined in a stepwise pattern, with RBD patients having lower intensity than controls (0.837 vs. 0.877, P = 0.01) but higher than PD patients (0.837 vs. 0.765, P < 0.001).InterpretationOver one quarter of RBD patients have abnormal substantia nigra SWI reminiscent of Parkinson’s, which is associated with a greater dopaminergic deficit. This modality may help enrich neuroprotective trials with early converters.

The Effect of Sertoli Cells on Xenotransplantation and Allotransplantation of Ventral Mesencephalic Tissue in a Rat Model of Parkinson's Disease.

Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson’s disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [18F] DOPA and [18F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [18F]DOPA and [18F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats.

Decreased Striatal Vesicular Monoamine Transporter Type 2 Correlates With the Nonmotor Symptoms in Parkinson Disease.

Nonmotor symptoms (NMS) are critical players in the patients' quality of life in Parkinson disease (PD). Vesicular monoamine transporter type 2 (VMAT2) has been reported owing to a role in affecting dopamine neurons in the striatum. Therefore, this study set out to characterize the relationship between VMAT2 distribution in the striatum in relation to the NMS in PD. Totally, 21 age-matched normal controls and 37 patients with PD in the moderate stages were included, followed by examination using F-DTBZ (F-AV133) PET/CT. The specific uptake ratio (SUR) of each striatal subregion was then determined with the occipital cortex as the reference background region. The overall NMSs of each individual patient were evaluated. Finally, the role of the striatal SURs in the clinical symptom scores were evaluated through the application of a Spearman correlation analysis as well as a multivariable stepwise regression analysis. Patients with PD, particularly those at a more advanced stage, exhibited a more pronounced reduction in SURs in the bilateral putamen and caudate nucleus (P < 0.05, vs healthy controls). Meanwhile, patients at more advanced PD stages were found to have significantly worse scores in NMS except cognitive function. The Spearman correlation analysis demonstrated that NMS scores, with the exception of cognition scores, were correlated with striatal SURs (P < 0.05). The key findings of the study identified a correlation between decreased striatal VMAT2 with a broad spectrum of NMS in patients with PD, highlighting the association between diminished dopamine supply and the development of NMS in PD.

Efficacy of ruthenium coordination complex-based Rutherrin in a preclinical rat glioblastoma model.

BackgroundGlioblastoma is an aggressive brain cancer in adults with a grave prognosis, aggressive radio and chemotherapy provide only a 15 months median survival.MethodsWe evaluated the tolerability and efficacy of the Ruthenium-based photosensitizer TLD-1433 with apo-Transferrin (Rutherrin) in the rat glioma 2 (RG-2) model. The specific tumor uptake ratio and photodynamic therapy (PDT) threshold of the rat glioblastoma and normal brain were determined, survival and CD8+T-cell infiltration post-therapy were analyzed. Results were compared with those obtained for 5-aminolevulinic acid (ALA)-induced Protoporphyrin IX (PpIX)-mediated photodynamic therapy in the same animal model. As both photosensitizers have different photophysical properties, the number of absorbed photons required to achieve an equal cell kill was determined for in vitro and in vivo studies.ResultsA significantly lower absorbed energy was sufficient to achieve LD50 with Rutherrin versus PpIX-mediated PDT. Rutherrin provides a higher specific uptake ratio (SUR) >20 in tumors versus normal brain, whereas the SUR for ALA-induced PpIX was 10.6. To evaluate the short-term tissue response in vivo, enhanced T2-weighted magnetic resonance imaging (MRI) provided the spatial extent of edema, post PpIX-PDT at twice the cross-section versus Rutherrin-PDT suggesting reduced nonspecific damage, typically associated with a secondary wave of neuronal damage. Following a single therapy, a significant survival increase was observed in rats bearing glioma for PDT mediated by Rutherrin versus PpIX for the selected treatment conditions. Rutherrin-PDT also demonstrated an increased CD8+T-cell infiltration in the tumors.ConclusionRutherrin-PDT was well tolerated providing a safe and effective treatment of RG-2 glioma.

Increased Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Expression in Adolescent Brain Development: A Longitudinal Micro-PET/CT Study in Rodent.

Background: Brain development and maturation in adolescence is a complex process with active changes of metabolic and neurotransmission pathways. Positron emission tomography (PET) is a useful imaging modality for tracking metabolic and functional changes in adolescent brain. In this study, changes of glucose metabolism, expression of vesicular monoamine transporter 2 and dopamine transporter during adolescent brain development in rats were investigated with PET/CT.Methods: A longitudinal PET/CT study of age-dependent changes of VMAT2, DAT and glucose metabolism in adolescent brain was conducted in a group of Wistar rats (n = 6) post sequential intravenous injection of 18F-PF-(+)-DTBZ, 11C-CFT, and 18F-FDG, respectively. PET acquisition was performed at 2, 4, 9, and 12 months of age. Radiotracer uptake in different brain regions, including the striatum, cerebellum, and hippocampus, were quantified and recorded as Standardized uptake value (SUV) and striatal specific uptake ratio (SUVR: SUV in brain regions/SUV in cerebellum).Results: Variable uptake of 18F-PF-(+)-DTBZ and 11C-CFT were detected, with highest level uptake in the striatum and accumbens. There was significant age-dependent increase of 18F-PF-(+)-DTBZ and 11C-CFT uptake in the striatum from 2 months of age (SUV: 1.36 ± 0.22, 1.37 ± 0.39, respectively), to 4 months (SUV: 2.22 ± 0.29, 2.04 ± 0.33), 9 months (1.98 ± 0.34, 2.09 ± 0.18), 12 months (SUV: 1.93 ± 0.19, 2.00 ± 0.17) of age, SUV of 18F-FDG also increased from 2 months of age to older ages (SUV in the striatum: 3.71 ± 0.78 at 2 month, 5.28 ± 0.81, 5.14 ± 0.73, 4.94 ± 0.50 at 4, 9, 12 month, respectively).Conclusion: Age-dependent increases of striatal of 18F-FDG, 18F-PF-(+)-DTBZ, and 11C-CFT uptake were detected in rats from 2 to 4 month of age, demonstrating striatal development presents over the first 4 months of age. Four months of age can be considered a safe threshold to launch brain disease studies for exclusion of confusion of continuing tissue development. These findings support further investigation of age-dependent changes in expression of DAT, VMAT2, and glucose metabolism for their potential use as a new imaging biomarker for study of brain development and functional maturation.

Dopamine Transporter maging with Tc-99m TRODAT-1 SPECT in Parkinson's isease and its orrelation with linical isease everity.

Objective(s):To evaluate the role of Tc-99m TRODAT-1 Single Photon Emission Computed Tomography (SPECT) in Parkinson’s Disease (PD) by assessing the correlation of clinical disease severity, disease duration and age at onset of disease with specific uptake ratio of Tc-99m TRODAT-1 in striatum. Methods:The study included 63 patients in age range of 40-72 years with clinical diagnosis of PD and nine controls. Clinical history of patients was obtained regarding age at onset of disease and disease duration. Disease severity in each patient was assessed using H and Y stage and UPDRS. Tc-99m TRODAT-1 SPECT was performed and specific uptake ratios were calculated for six regions in bilateral striata, caudate nuclei and putamina. Difference in specific uptake ratios between different stages of disease was analyzed for statistical significance. Specific uptake ratios were correlated with UPDRS, motor score of UPDRS, duration of disease and age at onset of disease using Pearson’s correlation co-efficient.Results:Median specific uptake ratio was found to be least in contralateral putamen for all H and Y stages. There was a statistically significant difference between specific uptake ratios of controls vs stage 1, stage 1 vs 2, 1 vs 3, 1 vs 4, and 2 vs 4 for all 6 regions. The difference in uptake ratio between 3 and 4 H and Y stages was significant only for contralateral regions. There was no significant difference in uptake ratio between 2 and 3 H and Y stages. The uptake ratios showed a strong negative correlation with UPDRS and motor score, a weak negative correlation with duration of disease and no significant correlation with age at onset of disease. Conclusion:We conclude that Tc-99m TRODAT-1 SPECT can be used to assess the disease severity in PD patients.

Quantitative study of 18F-(+)DTBZ image: comparison of PET template-based and MRI based image analysis

[18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-(+)DTBZ) is a recently developed PET tracer to investigate the vesicular monoamine transporter type 2 (VMAT2) activity in measuring dopaminergic degeneration in vivo and monitoring the severity of Parkinson’s disease (PD). However, manual drawing of the striatal regions is time consuming and prone to human bias. In the current study, we developed an automated method to quantify the signals of the striatum on 18F-(+)DTBZ images. 39 patients with PD and 26 controls were enrolled. Traditional brain magnetic resonance imaging (MRI) and 18F-(+)DTBZ PET were acquired. Both indirect normalization of native PET images to the standard space through individual brain MRI and directly coregistration of native images to the transporter-specific PET template in standard space were performed. Specific uptake ratios (SURs) in 10 predefined regions were used as indicators of VMAT2 activities to correlate with motor severity. Our results showed patients with PD had significant lower SURs in the bilateral putamina, caudates and globus pallidi than controls. SURs in the caudate and putamen were significantly correlated with motor severity. The contralateral putaminal region performed best in discriminating between PD patients and controls. Finally, the results from the application of the 18F-(+)DTBZ PET template were comparable to those derived from the traditional MRI based method. Thus, 18F-(+)DTBZ PET imaging holds the potential to effectively differentiate PD patients from controls. The 18F-(+)DTBZ PET template-based method for automated quantification of presynaptic VMAT2 transporter density is easier to implement and may facilitate efficient, robust and user-independent image analysis.

Impact of quantitative index derived from 123I-FP-CIT-SPECT on reconstruction with correction methods evaluated using a 3D-striatum digital brain phantom.

We evaluated quantitation accuracy of the specific binding ratio (SBR) and specific uptake ratio (SUR) of dopamine transporter for various correction methods by using a novel three-dimensional striatum digital brain (3D-SDB) phantom comprised of segments containing the striatum, ventricle, brain parenchyma, and skull bone extracted from T2-weighted MR images. A process image was reconstructed by projection data sets with blurring, scatter, and attenuation from 3D-SDB phantom data. A 3D-iterative reconstruction algorithm was used without correction (OSEM), or with scatter (SC), attenuation (AC), AC + SC (ACSC), AC + resolution recovery (RR; ACRR), SC + RR (SCRR), AC + SC + RR (ACSCRR), AC + SC + RR + partial volume (PVC; ACSCRRP), and AC + SC + RR + PVC + ventricle (ACSCRRPV). Data were then quantified using SBR and SUR. Differences between measured and true SBR values were (in order): ACSCRR < ACSC < ACRR < AC < SCRR < SC < OSEM: the maximal error was 45.3%. The trend of differences between measured and true SUR values was similar to that of SBR; maximal error was 65%. The ACSCRR-corrected SUR, which was closer to the true value, was underestimated by 30.4%. However, the ACSCRRP-corrected SUR was underestimated by a maximum of 22.5%. The SUR in the ACSCRRPV was underestimated by 6.2%. The accuracy of quantitation was improved using various types of compensation and correction. Accuracy improved more for the SUR when PVC and ventricle correction were added.

Optimization of the reconstruction parameters in [123I]FP-CIT SPECT

The aim of this work was to obtain a set of parameters to be applied in [123I]FP-CIT SPECT reconstruction in order to minimize the error between standardized and true values of the specific uptake ratio (SUR) in dopaminergic neurotransmission SPECT studies. To this end, Monte Carlo simulation was used to generate a database of 1380 projection data-sets from 23 subjects, including normal cases and a variety of pathologies. Studies were reconstructed using filtered back projection (FBP) with attenuation correction and ordered subset expectation maximization (OSEM) with correction for different degradations (attenuation, scatter and PSF). Reconstruction parameters to be optimized were the cut-off frequency of a 2D Butterworth pre-filter in FBP, and the number of iterations and the full width at Half maximum of a 3D Gaussian post-filter in OSEM. Reconstructed images were quantified using regions of interest (ROIs) derived from Magnetic Resonance scans and from the Automated Anatomical Labeling map. Results were standardized by applying a simple linear regression line obtained from the entire patient dataset. Our findings show that we can obtain a set of optimal parameters for each reconstruction strategy. The accuracy of the standardized SUR increases when the reconstruction method includes more corrections. The use of generic ROIs instead of subject-specific ROIs adds significant inaccuracies. Thus, after reconstruction with OSEM and correction for all degradations, subject-specific ROIs led to errors between standardized and true SUR values in the range [−0.5, +0.5] in 87% and 92% of the cases for caudate and putamen, respectively. These percentages dropped to 75% and 88% when the generic ROIs were used.