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.

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.

Trospium Chloride Transport by Mouse Drug Carriers of the Slc22 and Slc47 Families.

BACKGROUND: The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. METHOD: In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. RESULTS: Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP+ transport with Km of 60.0 µM that was inhibited by the drugs topotecan, acyclovir, and levofloxacin. CONCLUSION: TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.

Laterality of specific binding ratios on DAT-SPECT for differential diagnosis of degenerative parkinsonian syndromes.

Motor symptoms of Parkinson's disease (PD) occur unilaterally and progress with asymmetry, while progressive supranuclear palsy (PSP) and multiple system atrophy of the parkinsonism subtype (MSA-P) lack this tendency. We assessed the laterality of specific binding ratios (SBRs) on dopamine transporter single-photon emission computed tomography (DAT-SPECT) for the differential diagnosis of these diseases in 311 PD, 33 PSP, 20 MSA-P, and 137 control patients. The average SBR in PD was higher than that in PSP (P = 0.035). Compared with Hoehn-Yahr (HY) stages, the average SBR in PD with HY stage I was only higher than that in PSP (P < 0.001). SBR laterality in PD with HY stage I was significantly higher than that in PSP (P = 0.001). This difference was not observed in PD with HY stage II. The average and laterality of SBRs in MSA-P were similar to those in PD and PSP. The asymmetry indices were similar among PD, PSP, and MSA-P. These data suggest that PSP shows a pattern of SBRs different from that in PD, attributed to HY stage I in PD. The limited usefulness of DAT-SPECT may be explained by the low discrimination between PD with bilateral motor symptoms and PSP.

Impact of aging on semiquantitative uptake parameters in normal rated clinical baseline [123I]Ioflupane single photon emission computed tomography/computed tomography.

OBJECTIVES: Studies investigating the age-related impact on dopamine transporter binding have previously omitted the use of attenuation correction by computed tomography (CT). We aimed to explore the impact of age and gender on dopamine transporter binding on [I]Ioflupane single photon emission CT (SPECT) imaging with simultaneously acquired CT. METHODS: Three hundred forty-two patients with clinically uncertain parkinsonian syndrome underwent [I]-Ioflupane SPECT/CT with CT-based attenuation correction. Two nuclear medicine physicians independently performed a visual evaluation of all scans and only visibly normal scans were included for further analysis. Moreover, the results of a fully automatic semiquantitative evaluation method were recorded. Thereafter, the obtained [I]Ioflupane binding ratio and the hemispheric asymmetry index were correlated with age and sex. RESULTS: Patient age range was 41-80 years with a balanced distribution over decades. Of 342 patients, 133 (38.9%, 66 females, median age, 64 years) were considered visually normal by both observers on the SPECT/CT images. A significant inverse correlation between age and [I]Ioflupane binding ratios in the striata (R = -0.38; P < 0.001), putamina (R = -0.39; P < 0.001) and caudate nuclei (R = -0.3; P < 0.001) was demonstrated. Linear regression of all included subjects demonstrated an average decrease of 0.19 per decade in the striatal binding ratio (6.6%). No significant sex differences were found in striatal binding ratios (P = 0.86). Moreover, no significant correlation was observed between age and striatal asymmetry index (r = 0.12; P = 0.16). CONCLUSION: In the present largest single-center analysis investigating [I]Ioflupane SPECT/CT in patients with clinical uncertain parkinsonian syndrome, a dopamine transporter loss of 6.6% per decade in visually normal scans was recorded.

Assisted Diagnosis of Parkinsonism Based on the Striatal Morphology.

Parkinsonism is a clinical syndrome characterized by the progressive loss of striatal dopamine. Its diagnosis is usually corroborated by neuroimaging data such as DaTSCAN neuroimages that allow visualizing the possible dopamine deficiency. During the last decade, a number of computer systems have been proposed to automatically analyze DaTSCAN neuroimages, eliminating the subjectivity inherent to the visual examination of the data. In this work, we propose a computer system based on machine learning to separate Parkinsonian patients and control subjects using the size and shape of the striatal region, modeled from DaTSCAN data. First, an algorithm based on adaptative thresholding is used to parcel the striatum. This region is then divided into two according to the brain hemisphere division and characterized with 152 measures, extracted from the volume and its three possible 2-dimensional projections. Afterwards, the Bhattacharyya distance is used to discard the least discriminative measures and, finally, the neuroimage category is estimated by means of a Support Vector Machine classifier. This method was evaluated using a dataset with 189 DaTSCAN neuroimages, obtaining an accuracy rate over 94%. This rate outperforms those obtained by previous approaches that use the intensity of each striatal voxel as a feature.

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

Retinal thinning associates with nigral dopaminergic loss in de novo Parkinson disease.

OBJECTIVE: To analyze the relationship between retinal thinning and nigral dopaminergic loss in de novo Parkinson disease (PD). METHODS: Forty-nine patients with PD and 54 age-matched controls were analyzed. Ophthalmologic examination and macula optical coherence tomography scans were performed with additional microperimetry, N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI scans were done in patients with PD only. Retinal layer thickness and volume were measured in subfields of the 1-, 2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy Study circle and compared in patients with PD and controls. Correlation of inner retinal layer thinning with microperimetric response was examined in patients with PD, and the relationships between retinal layer thickness and dopamine transporter densities in the ipsilateral caudate, anterior and posterior putamen, and substantia nigra were analyzed. RESULTS: Retinal layer thinning was observed in the temporal and inferior 2.22-mm sectors (false discovery rate-adjusted p < 0.05) of drug-naive patients with PD, particularly the inner plexiform and ganglion cell layers. The thickness of these layers in the inferior 2.22-mm sector showed a negative correlation with the Hoehn and Yahr stage (p = 0.032 and 0.014, respectively). There was positive correlation between macular sensitivity and retinal layer thickness in all 3.45-mm sectors, the superior 2.22-mm sector, and 1-mm circle (p < 0.05 for all). There was an association between retinal thinning and dopaminergic loss in the left substantia nigra (false discovery rate-adjusted p < 0.001). CONCLUSION: Retinal thinning is present in the early stages of PD, correlates with disease severity, and may be linked to nigral dopaminergic degeneration. Retinal imaging may be useful for detection of pathologic changes occurring in early PD.

Whole-Body Biodistribution and Dosimetry of the Dopamine Transporter Radioligand 18F-FE-PE2I in Human Subjects.

18F-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl-phenyl) nortropane (18F-FE-PE2I) was recently developed and has shown adequate affinity and high selectivity for the dopamine transporter (DAT). Previous studies have shown promising results for 18F-FE-PE2I as a suitable radioligand for DAT imaging. In this study, we investigated the whole-body biodistribution and dosimetry of 18F-FE-PE2I in healthy volunteers to support its utility as a suitable PET imaging agent for the DAT. Methods: Five healthy volunteers were given a mean activity of 2.5 MBq/kg, and 3 PET scans, head to thigh, were performed immediately after injection followed by 4 whole-body PET/CT scans between 0.5 and 6 h after injection. Blood samples were drawn in connection with the whole-body scans, and all urine was collected until 6 h after injection. Volumes of interest were delineated around 17 organs on all images, and the areas under the time-activity curves were calculated to obtain the total number of decays in the organs. The absorbed doses to organs and the effective dose were calculated using the software IDAC. Results: The highest activity concentration was observed in the liver (0.9%-1.2% injected activity/100 g) up to 30 min after injection. At later time points, the highest concentration was seen in the gallbladder (1.1%-0.1% injected activity/100 g). The activity excreted with urine ranged between 23% and 34%, with a mean of 28%. The urinary bladder received the highest absorbed dose (119 µGy/MBq), followed by the liver (46 µGy/MBq). The effective dose was 23 µSv/MBq (range, 19-28 µSv/MBq), resulting in an effective dose of 4.6 mSv for an administered activity of 200 MBq. Conclusion: The effective dose is within the same order of magnitude as other commonly used PET imaging agents as well as DAT agents. The reasonable effective dose, together with the previously reported favorable characteristics for DAT imaging and quantification, indicates that 18F-FE-PE2I is a suitable radioligand for DAT imaging.

Improved 123I-Ioflupane Binding After Immunotherapy in Anti-NAE Antibody-Positive Hashimoto Encephalopathy That Clinically Mimicked Multiple System Atrophy.

We describe an 84-year-old man with anti-NH2-terminal of α-enolase antibody-positive Hashimoto encephalopathy that clinically mimicked multiple system atrophy who underwent investigation by dopamine transporter SPECT before and after immunotherapy. Before treatment, dopamine transporter SPECT showed reduced striatal I-ioflupane binding, with a mean specific binding ratio of 2.42, even though he had no apparent parkinsonism. After immunotherapy, mean specific binding ratio was improved to 3.22. Dopamine transporter SPECT was useful in this case to detect subclinical striatal dysfunction, and evaluation both before and after immunotherapy helped to distinguish between neurodegenerative disease and neuroimmunological disorder.

Availability of dopamine transporters in heroin-dependent subjects: A 18F-FECNT PET imaging study.

This study was to reconfirm the reduced dopamine transporter (DAT) availability in heroin-dependent subjects and validate the use of 2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane (18F-FECNT) as a PET radiotracer to assess the changes of striatal DAT in drug addicted subjects. Herein, we assessed DAT standardized uptake values (SUV) of 18F-FECNT in the striatum and cerebellum of 20 heroin-dependent subjects and 10 healthy controls and analyzed the correlation between DAT availability and heroin withdrawal symptom scores and anxiety/depression rating scales in heroin-dependent subjects, as well as the relationship between the withdrawal symptoms scores and age. The striatal DAT availability in heroin-dependent subjects was significantly lower (by ~15.7-17.6%) than that in healthy controls. Age was positively related to heroin withdrawal symptom scores. The withdrawal symptom scores in older patients (Age: 49.5±2.5) were significantly higher (by ~20%) than those in younger patients (Age: 30.9±4.8). These results confirm that chronic heroin use induces striatal DAT reduction, suggesting that 18F-FECNT could be used as an alternative PET imaging radioligand for in vivo imaging of DAT in drug addicted subjects. Moreover, older patients might suffer more severe withdrawal symptoms than younger patients, suggesting that older patients with heroin withdrawal could be given more medication.

Unilaterally Decreased Striatal Dopamine Transporter Caused by Venous Anomaly.

We describe a finding of unilaterally decreased binding of I-ioflupane in the basal ganglia in a 78-year-old woman that could be attributed to an underlying developmental venous anomaly.

Trospium chloride is absorbed from two intestinal "absorption windows" with different permeability in healthy subjects.

Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30mg/250ml=[I]2) for 6h and after swallowing 30mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ∼10h) after gastric infusion involving two processes with different input rates, peaking at about 3h and 7h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two "windows" located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1.

Scan without evidence of dopaminergic deficit: A 10-year retrospective study.

INTRODUCTION: 123I-ioflupane SPECT is a powerful method to assess nigrostriatal dopamine system integrity. Several independent studies have shown that 1-15% of patients with suspected degenerative parkinsonism, mainly PD, have scans without evidence of dopaminergic deficit (SWEDD). It has been proposed that most SWEDD patients either present with a non-degenerative condition mimicking PD, such as atypical tremor or dystonia, or demonstrate an abnormal scan when repeated later. We here hypothesized that scan interpretation methods may also play a crucial yet underestimated role in this issue. METHODS: We previously established age-dependent reference values of striatal uptake by analyzing scans from a cohort of patients with non-degenerative conditions. We then studied a large population with well-established degenerative parkinsonism (N = 410, 80% with PD), using identical imaging protocol, to evaluate the prevalence of patients with normal scans based on routine visual assessment. Each scan was eventually reassessed using the same automated method as for controls and a detailed 3D analysis. RESULTS: Ten potential SWEDD cases (2.4%) were identified. However, both reassessment methods independently showed that these scans were all outside reference limits and/or visually abnormal when reexamined carefully, except for one case (0.2%) with corticobasal syndrome. CONCLUSION: SPECT misinterpretation emerges as an important contributor to the SWEDD population, suggesting that suspected SWEDD cases should prompt not only a serious diagnosis challenge but, equally important, a detailed scan reassessment. True SWEDD cases seem extremely rare in degenerative parkinsonism. We propose that the very concept of SWEDD is more confusing than helpful and should be definitely abandoned.

PET imaging of dopamine transporters with [(18)F]FE-PE2I: Effects of anti-Parkinsonian drugs.

PURPOSE: This study aimed to assess the striatal [(18)F]FE-PE2I binding and the immunohistochemical stain of tyrosine hydroxylase (TH) in the striatum, and to evaluate the effects of therapeutic drugs on [(18)F]FE-PE2I binding. METHODS: Dynamic PET/CT of [(18)F]FE-PE2I was performed in Parkinson's disease (PD) rat models, induced by the unilateral injection of 6-OHDA into the striatum. A simplified reference tissue model method was used to calculate the striatal binding potential (striatal BPND). Each of the four normal rats was pretreated with pramipexole, amantadine, and escitalopram 30 min before [(18)F]FE-PE2I injection. The effect of L-DOPA combined with benserazide was assessed in the normal and PD rats. RESULTS: The BPND was significantly lower in the lesioned striatum than in the striatum of the normal rats. After the pretreatment with pramipexole, amantadine, and escitalopram, the values of the striatal BPND did not differ from those of the controls. The pretreatment with L-DOPA/benserazide, however, significantly reduced the striatal BPND. The striatal BPND of the PD rats with L-DOPA/benserazide pretreatment was not different from that of the same PD rats with placebo treatment. CONCLUSION: [(18)F]FE-PE2I may be used as a radioligand for the in-vivo imaging of the DAT. In the normal rats, [(18)F]FE-PE2I binding is unaffected by pramipexole, amantadine, and escitalopram. L-DOPA/benserazide does not affect the striatal [(18)F]FE-PE2I binding in PD rats.

Quantitative Analysis of ¹8F-(E)-N-(3-Iodoprop-2-Enyl)-2ß-Carbofluoroethoxy-3ß-(4'-Methyl-Phenyl) Nortropane Binding to the Dopamine Transporter in Parkinson Disease.

UNLABELLED: (18)F-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl-phenyl) nortropane ((18)F-FE-PE2I) is a recently developed radioligand for the in vivo quantification of the dopamine transporter (DAT) in the striatum and substantia nigra (SN). The aim of this study was to examine the suitability of (18)F-FE-PE2I as a tool for imaging the nigrostriatal pathway in Parkinson disease (PD) with PET. METHODS: Ten PD patients (9 men and 1 woman; mean age ± SD, 60 ± 9 y; Hoehn and Yahr, 1-2; Unified Parkinson Disease Rating Scale motor, 18.9 ± 6.7) and 10 controls (9 men and 1 woman; mean age ± SD, 60 ± 7 y) were included. PET measurements with (18)F-FE-PE2I were conducted for 93 min using the High-Resolution Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction, and radiometabolite composition in PD patients and controls. Regions of interest for the caudate, putamen, ventral striatum, SN, and cerebellum were drawn on coregistered MR images. The outcome measure was the binding potential (BP(ND)) estimated with the simplified reference tissue model and the Logan graphical analysis, using the cerebellum as a reference region. Time stability of BP(ND) was examined to define the shortest acquisition protocol for quantitative studies. The wavelet-aided parametric imaging method was used to obtain high-resolution BP(ND) images to compare DAT availability in the striatum and SN in PD patients and control subjects. Group differences were assessed with the unpaired t test (P < 0.05). RESULTS: Parent, radiometabolite fractions, plasma concentration, and cerebellar uptake of (18)F-FE-PE2I did not differ significantly between PD patients and controls. Stable estimates of BP(ND) (<8% of the 93-min value) were obtained with the simplified reference tissue model using approximately 66 min of data. BP(ND) values in PD patients were significantly lower than those in controls (P < 0.05) in the caudate (2.54 ± 0.79 vs. 3.68 ± 0.56), putamen (1.39 ± 1.04 vs. 4.41 ± 0.54), ventral striatum (2.26 ± 0.93 vs. 3.30 ± 0.46), and SN (0.46 ± 0.20 vs. 0.68 ± 0.15). CONCLUSION: (18)F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metabolism in controls and PD patients, suitability of the cerebellum as a reference region, and accuracy of quantification using approximately 66 min of PET data are advantages for noninvasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both the striatum and the SN, supporting the utility of (18)F-FE-PE2I as an imaging tool of the nigrostriatal pathway.

Evaluation of an Objective Striatal Analysis Program for Determining Laterality in Uptake of ¹²³I-Ioflupane SPECT Images: Comparison to Clinical Symptoms and to Visual Reads.

UNLABELLED: An automated objective striatal analysis (OSA) software program was applied to dopamine transporter (123)I-ioflupane images acquired on subjects with varying severities of parkinsonism. The striatal binding ratios (SBR) of the left and right putamina (relative to the occipital lobe) were computed, and the laterality of that measure was compared with clinical symptoms and visual reads. The objective over-read of OSA was evaluated as an aid in confirming the laterality of disease onset. METHODS: One hundred one (123)I-ioflupane scans were acquired on clinically referred subjects. SPECT images were analyzed using the OSA software, which locates the slices containing the striatal and background (occipital) structures, positions regions over the left and right caudate nuclei and putamina, and calculates the background-subtracted SBR. Seven images were uninterpretable because of patient motion or lack of visualization of the striatum. The remaining 94 scans were analyzed with OSA. Differences between left and right putaminal SBR ranged from 0% to 36.6%, with a mean of 11.4%. When the difference between the SBR of the left and right putamina was greater than 6%, the lower side was taken as the side of onset. Left-to-right differences less than 6% were considered to be nonlateralizing (symmetric). The 94 scans were reviewed independently by 3 masked expert readers. By majority consensus, abnormal findings were seen on 67 of the 94 scans, of which 46 had available clinical findings. RESULTS: Clinically, 34 subjects presented with lateralized tremors and 12 with symmetric or no tremors. Of the 34 cases of clinically lateralized tremors, 26 (76%) were concordant with the OSA findings, 5 were disparate with OSA (15%), and in 3 the OSA results were symmetric (9%). For the same 34 patients, the visual reads were concurrent with clinical tremor findings in 24 cases (71%), 1 was disparate (3%), and 9 visual reads were symmetric (26%). Of the 9 scans deemed symmetric by readers, 4 were correctly lateralized by OSA, and of the 3 symmetric OSA results, 2 were correctly lateralized visually. CONCLUSION: The OSA program may be a helpful aid in the interpretation of (123)I-ioflupane SPECT images for determining laterality representing the asymmetric loss of dopamine transporters in the striata. OSA offers an objective, reproducible over-read evaluation for the laterality of onset in Parkinson disease.

Docking and SAR studies of calystegines: binding orientation and influence on pharmacological chaperone effects for Gaucher's disease.

We report on the identification of the required configuration and binding orientation of nor-tropane alkaloid calystegines against ß-glucocerebrosidase. Calystegine B2 is a potent competitive inhibitor of human lysosomal ß-glucocerebrosidase with Ki value of 3.3 µM. A molecular docking study revealed that calystegine B2 had a favorable van der Waals interactions (Phe128, Trp179, and Phe246) and the hydrogen bonding (Glu235, Glu340, Asp127, Trp179, Asn234, Trp381 and Asn396) was similar to that of isofagomine. All calystegine isomers bound into the same active site as calystegine B2 and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. Calystegine A3 bound to ß-glucocerebrosidase with the same orientations as calystegine B2 (Type 1), while calystegine B3 and B4 had different binding orientations (Type 2). It is noteworthy that Type 1 orientated calystegines B2 and A3 effectively stabilized ß-glucocerebrosidase, and consequently increased intracellular ß-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines B3 and B4 could not keep the enzyme activity. These results clearly indicate that the binding orientations of calystegines are changed by the configuration of the hydroxyl groups on the nor-tropane ring and the suitable binding orientation is a requirement for achieving a strong affinity to ß-glucocerebrosidase.

Quantification of dopamine transporter density with [18F]FECNT PET in healthy humans.

INTRODUCTION: Fluorine-18 labeled 2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([(18)F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [(18)F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [(18)F]FECNT for quantification of DAT density in healthy human brain. METHODS: Twelve healthy volunteers underwent 180 min dynamic [(18)F]FECNT PET imaging including sampling of arterial blood. Regional time-activity curves were extracted from the caudate, putamen and midbrain including a reference region placed in the cerebellum. Binding potential, BPND, was calculated for all regions using kinetic parameters estimated from compartmental and Logan graphical model fits to the time-activity data. Simulations were performed to determine whether the compartment model could reliably fit time-activity data over a range of BPND values. RESULTS: The kinetics of [(18)F]FECNT were well-described by the reversible 2-tissue arterial input and full reference tissue compartment models. Calculated binding potentials in the caudate, putamen and midbrain were in good agreement between the arterial input model, reference tissue model and the Logan graphical model. The distribution volume in the cerebellum did not reach a plateau over the duration of the study, which may be a result of non-specific binding in the cerebellum. Simulations that included non-specific binding show that the reference and arterial input models are able to estimate BPND for DAT densities well below that observed in normal volunteers. CONCLUSION: The kinetics of [(18)F]FECNT in human brain are well-described by arterial input and reference tissue compartment models. Measured and simulated data show that BPND calculated with reference tissue model is proportional to BPND calculated from the arterial input model.