Striatal Binding Ratios Research Articles

High-Accuracy Classification of Parkinson's Disease Through Shape Analysis and Surface Fitting in 123I-Ioflupane SPECT Imaging.

Early and accurate identification of Parkinsonian syndromes (PS) involving presynaptic degeneration from nondegenerative variants such as scans without evidence of dopaminergic deficit (SWEDD) and tremor disorders is important for effective patient management as the course, therapy, and prognosis differ substantially between the two groups. In this study, we use single photon emission computed tomography (SPECT) images from healthy normal, early PD, and SWEDD subjects, as obtained from the Parkinson's Progression Markers Initiative (PPMI) database, and process them to compute shape- and surface-fitting-based features. We use these features to develop and compare various classification models that can discriminate between scans showing dopaminergic deficit, as in PD, from scans without the deficit, as in healthy normal or SWEDD. Along with it, we also compare these features with striatal binding ratio (SBR)-based features, which are well established and clinically used, by computing a feature-importance score using random forests technique. We observe that the support vector machine (SVM) classifier gives the best performance with an accuracy of 97.29%. These features also show higher importance than the SBR-based features. We infer from the study that shape analysis and surface fitting are useful and promising methods for extracting discriminatory features that can be used to develop diagnostic models that might have the potential to help clinicians in the diagnostic process.

Gray matter correlates of dopaminergic degeneration in Parkinson's disease: A hybrid PET/MR study using (18) F-FP-CIT.

Dopaminergic degeneration is a hallmark of Parkinson's disease (PD), which causes various symptoms affected by corticostriatal circuits. So far, the relationship between cortical changes and dopamine loss in the striatum is unclear. Here, we evaluate the gray matter (GM) changes in accordance with striatal dopaminergic degeneration in PD using hybrid PET/MR. Sixteen patients with idiopathic PD underwent (18) F-FP-CIT PET/MR. To measure dopaminergic degeneration in PD, binding ratio (BR) of dopamine transporter in striatum was evaluated by (18) F-FP-CIT. Voxel-based morphometry (VBM) was used to evaluate GM density. We obtained voxelwise correlation maps of GM density according to the striatal BR. Voxel-by-voxel correlation between BR maps and GM density maps was done to evaluate region-specific correlation of striatal dopaminergic degeneration. There was a trend of positive correlation between striatal BR and GM density in the cerebellum, parahippocampal gyri, and frontal cortex. A trend of negative correlation between striatal BR and GM density in the medial occipital cortex was found. Voxel-by-voxel correlation revealed that the positive correlation was mainly dependent on anterior striatal BR, while posterior striatal BR mostly showed negative correlation with GM density in occipital and temporal cortices. Decreased GM density related to anterior striatal dopaminergic degeneration might demonstrate degeneration of dopaminergic nonmotor circuits. Furthermore, the negative correlation could be related to the motor circuits of posterior striatum. Our integrated PET/MR study suggests that the widespread structural progressive changes in PD could denote the cortical functional correlates of the degeneration of striatal dopaminergic circuits. Hum Brain Mapp 37:1710-1721, 2016. © 2016 Wiley Periodicals, Inc.

Design of a Multi-Pinhole Collimator for I-123 DaTscan Imaging on Dual-Headed SPECT Systems in Combination with a Fan-Beam Collimator.

For the 2011 FDA approved Parkinson's Disease (PD) SPECT imaging agent I-123 labeled DaTscan, the volume of interest (VOI) is the interior portion of the brain. However imaging of the occipital lobe is also required with PD for calculation of the striatal binding ratio (SBR), a parameter of significance in early diagnosis, differentiation of PD from other disorders with similar clinical presentations, and monitoring progression. Thus we propose the usage of a combination of a multi-pinhole (MPH) collimator on one head of the SPECT system and a fan-beam on the other. The MPH would be designed to provide high resolution and sensitivity for imaging of the interior portion of the brain. The fan-beam collimator would provide lower resolution but complete sampling of the brain addressing data sufficiency and allowing a volume-of-interest to be defined over the occipital lobe for calculation of SBR's. Herein we focus on the design of the MPH component of the combined system. Combined reconstruction will be addressed in a subsequent publication. An analysis of 46 clinical DaTscan studies was performed to provide information to define the VOI, and design of a MPH collimator to image this VOI. The system spatial resolution for the MPH was set to 4.7 mm, which is comparable to that of clinical PET systems, and significantly smaller than that of fan-beam collimators employed in SPECT. With this set, we compared system sensitivities for three aperture array designs, and selected the 3 × 3 array due to it being the highest of the three. The combined sensitivity of the apertures for it was similar to that of an ultra-high resolution fan-beam (LEUHRF) collimator, but smaller than that of a high-resolution fan-beam collimator (LEHRF). On the basis of these results we propose the further exploration of this design through simulations, and the development of combined MPH and fan-beam reconstruction.

DAT imaging and clinical biomarkers in relatives at genetic risk for LRRK2 R1441G Parkinson's disease.

The objective of this study was to study motor and nonmotor symptoms and striatal dopaminergic denervation, as well as the relationship between them, in a cohort of asymptomatic relatives of patients with Parkinson's disease (PD) with the R1441G-leucine-rich repeat kinase 2 mutation. Asymptomatic relatives of patients with PD and this mutation were tested for the presence of the mutation and evaluated for striatal, putamenal, and caudate dopaminergic transporters using (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single-photon emission computed tomography binding ratios. Clinical and neuropsychological evaluations including timed motor tests, a smell identification test, and global cognition, attention, executive, visuospatial, and memory functions as well as depression, constipation, and rapid eye movement sleep behavior disorder were also assessed. Twenty-seven carriers and 19 noncarriers were studied. Compared with noncarriers, mutation carriers had significantly lower (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan mean striatal (P = 0.03), mean putamenal (P = 0.01), and lowest putamenal (P = 0.01) binding ratios. Multiple linear regression analysis showed that the carrier status and the execution of timed tests significantly predicted striatal (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane binding. The proportion of variation accounted for by the regression model of these variables was 69% for the putamen and 53% for the caudate nucleus. Asymptomatic carriers of the R1441G-leucine-rich repeat kinase 2 mutation have evidence of dopaminergic nigrostriatal denervation, mainly in the putamen, which is associated with a decline in the execution of complex motor tests. These tests could be early indicators of the ongoing dopaminergic deficit in this group at risk of PD.

Loss of Dopamine Transporter Binding and Clinical Symptoms in Dementia With Lewy Bodies.

Little is known about the underlying mechanisms of clinical symptoms in dementia with Lewy bodies. The aim of this study was to explore the association between loss of striatal dopamine transporter binding and symptoms in dementia with Lewy bodies. Thirty-five patients with dementia with Lewy bodies underwent single-photon emission computerized tomography brain imaging with N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([(123) I]FP-CIT). Associations between striatal binding ratios and motor (UPDRS), psychiatric (Neuropsychiatric Inventory; [NPI]), and cognitive (Mini-Mental State Examination [MMSE] and neuropsychological tests) symptoms were assessed by linear regression analysis. The explorative analysis showed that the motor UPDRS was negatively associated with putamen dopamine transporter binding, whereas no association with striatal dopamine transporter binding was found for total NPI, hallucinations, apathy, depression, anxiety, and MMSE scores. However, in post-hoc analysis, executive impairment was positively associated with dopamine transporter loss after adjustment of age and gender. Dopamine deficiency in patients with dementia with Lewy bodies was associated with severity of motor symptoms, but did not correlate significantly with ratings of neurobehavioral disturbances or overall cognition.

Amphetamine decreases α2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain.

Background:The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands.Methods:We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [11C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [11C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys.Results:Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [11C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [11C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [11C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31–50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata.Conclusions:Together, these results indicate that [11C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.

Imaging prodromal Parkinson disease: the Parkinson Associated Risk Syndrome Study.

The purpose of this study is to evaluate the relative risk of abnormal dopamine transporter (DAT) imaging for subjects with and without hyposmia and the feasibility of acquiring a large, community-based, 2-tiered biomarker assessment strategy to detect prodromal Parkinson disease (PD). In this observational study, individuals without a diagnosis of PD, recruited through 16 movement disorder clinics, underwent tier 1 assessments (olfactory testing, questionnaires). Tier 2 assessments (neurologic examination, DAT imaging, and other biomarker assessments) were completed by 303 subjects. The main outcome of the study is to compare age-expected [(123)I]β-CIT striatal binding ratio in hyposmic and normosmic subjects. Tier 1 assessments were mailed to 9,398 eligible subjects and returned by 4,999; 669 were hyposmic. Three hundred three subjects (203 hyposmic, 100 normosmic) completed baseline evaluations. DAT deficit was present in 11% of hyposmic subjects compared with 1% of normosmic subjects. Multiple logistic regression demonstrates hyposmia (odds ratio [OR] 12.4; 95% confidence interval [CI] 1.6, 96.1), male sex (OR 5.5; 95% CI 1.7, 17.2), and constipation (OR 4.3; 95% CI 1.6, 11.6) as factors predictive of DAT deficit. Combining multiple factors (hyposmia, male sex, and constipation) increased the percentage of subjects with a DAT deficit to >40%. Subjects with DAT deficit who do not meet criteria for a diagnosis of PD can be identified by olfactory testing. Sequential biomarker assessment may identify those at risk of PD. Selecting hyposmic individuals enriches the population for DAT deficit, and combining hyposmia with other potential risk factors (male sex, constipation) increases the percentage of subjects with a DAT deficit compatible with prodromal PD.

Transcranial Sonography and 123I-FP-CIT Single Photon Emission Computed Tomography in Movement Disorders

Diagnosis of Parkinson's disease (PD) can be difficult in the early stages of the disease. The aim of the study described here was to assess the correlation between transcranial sonography (TCS) and 123I-FP-CIT ([123I]ioflupane, N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[123I]iodophenyl)nortropane) SPECT (single photon emission computed tomography) findings and the diagnosis of PD. A total of 49 patients were enrolled in the study: 29 patients with PD, 7 patients with other parkinsonian syndromes, 11 patients with essential tremor and 2 with psychogenic movement disorder. Substantia nigra echogenicity was measured using TCS. SPECT was performed using DaTSCAN ([123I]ioflupane). TCS and SPECT findings were correlated in 84% of patients, with κ = 0.62 (95% confidence interval: 0.38–0.86). TCS-measured substantia nigra echogenicity and SPECT-measured striatal binding ratio were negatively correlated (r = –0.326, p = 0.003). TCS/SPECT sensitivity, specificity and positive and negative predictive values for the diagnosis of PD were 89.7%/96.6%, 60.0%/70.0%, 76.5%/82.4% and 80.0%/93.3%, respectively. Both positive TCS and SPECT findings correlated significantly with the diagnosis of PD (κ = 0.52, 95% confidence interval: 0.27–0.76, and κ = 0.69, 95% confidence interval: 0.49–0.90, respectively).

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease.

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [(123)I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor.

Large-scale resting state network correlates of cognitive impairment in Parkinson's disease and related dopaminergic deficits.

Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with 123I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the “cognitive network” was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased prefronto-limbic processing, and was not associated with presynaptic striatal dopamine uptake. SBR ratios were negatively correlated with modularity of the “cognitive network,” suggesting integrative effects of the preserved nigrostriatal dopamine system on this circuitry.

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

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. 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. 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. 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.

Automatic classification and prediction models for early Parkinson’s disease diagnosis from SPECT imaging

Early and accurate diagnosis of Parkinson’s disease (PD) is important for early management, proper prognostication and for initiating neuroprotective therapies once they become available. Recent neuroimaging techniques such as dopaminergic imaging using single photon emission computed tomography (SPECT) with 123I-Ioflupane (DaTSCAN) have shown to detect even early stages of the disease. In this paper, we use the striatal binding ratio (SBR) values that are calculated from the 123I-Ioflupane SPECT scans (as obtained from the Parkinson’s progression markers initiative (PPMI) database) for developing automatic classification and prediction/prognostic models for early PD. We used support vector machine (SVM) and logistic regression in the model building process. We observe that the SVM classifier with RBF kernel produced a high accuracy of more than 96% in classifying subjects into early PD and healthy normal; and the logistic model for estimating the risk of PD also produced high degree of fitting with statistical significance indicating its usefulness in PD risk estimation. Hence, we infer that such models have the potential to aid the clinicians in the PD diagnostic process.

Value of Semiquantitative Analysis for Clinical Reporting of123I-2-β-Carbomethoxy-3β-(4-Iodophenyl)-N-(3-Fluoropropyl)Nortropane SPECT Studies

Clinical (123)I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ((123)I-FP-CIT) SPECT studies are commonly performed and reported using visual evaluation of tracer binding, an inherently subjective method. Increased objectivity can potentially be obtained using semiquantitative analysis. In this study, we assessed whether semiquantitative analysis of (123)I-FP-CIT tracer binding created more reproducible clinical reporting. A secondary aim was to determine in what form semiquantitative data should be provided to the reporter. Fifty-four patients referred for the assessment of nigrostriatal dopaminergic degeneration were scanned using SPECT/CT, followed by semiquantitative analysis calculating striatal binding ratios (SBRs) and caudate-to-putamen ratios (CPRs). Normal reference values were obtained using 131 healthy controls enrolled on a multicenter initiative backed by the European Association of Nuclear Medicine. A purely quantitative evaluation was first performed, with each striatum scored as normal or abnormal according to reference values. Three experienced nuclear medicine physicians then scored each striatum as normal or abnormal, also indicating cases perceived as difficult, using visual evaluation, visual evaluation in combination with SBR data, and visual evaluation in combination with SBR and CPR data. Intra- and interobserver agreement and agreement between observers and the purely quantitative evaluation were assessed using κ-statistics. The agreement between scan interpretation and clinical diagnosis was assessed for patients with a postscan clinical diagnosis available (n = 35). The physicians showed consistent reporting, with a good intraobserver agreement obtained for the visual interpretation (mean κ ± SD, 0.95 ± 0.029). Although visual interpretation of tracer binding gave good interobserver agreement (0.80 ± 0.045), this was improved as SBRs (0.86 ± 0.070) and CPRs (0.95 ± 0.040) were provided. The number of striata perceived as difficult to interpret decreased as semiquantitative data were provided (30 for the visual interpretation; 0 as SBR and CPR values were given). The agreement between physicians' interpretations and the purely quantitative evaluation showed that readers used the semiquantitative data to different extents, with a more experienced reader relying less on the semiquantitative data. Good agreement between scan interpretation and clinical diagnosis was seen. A combined approach of visual assessment and semiquantitative analysis of tracer binding created more reproducible clinical reporting of (123)I-FP-CIT SPECT studies. Physicians should have access to both SBR and CPR data to minimize interobserver variability.

Monoaminergic dysfunction in recreational users of dexamphetamine

Preclinical studies suggest that dexamphetamine (dAMPH) can lead to monoaminergic neurotoxicity. This exploratory study aimed to investigate effects of recreational dAMPH use on the dopamine (DA) and noradrenaline (NA) systems in humans. To that purpose, eight male abstinent dAMPH (26.0±4.0 years) users and 10 age- and IQ-matched male healthy control subjects (23.0±3.8) underwent neuropsychological testing sensitive to DAergic function and single photon emission computed tomography (SPECT) scanning with [123I]FP-CIT to determine striatal DA transporter (DAT) binding. In addition, changes in cerebral blood flow (CBF) induced by the DA/NA reuptake inhibitor methylphenidate (MPH) were measured using pharmacological magnetic resonance imaging (phMRI). Performance of dAMPH users was significantly worse on executive function and verbal memory tasks. Striatal DAT binding ratios were on average lower in dAMPH users (near-significant, p=0.05). In addition, CBF in control subjects decreased significantly in response to MPH in gray matter and basal ganglia, among which the striatum, thalamus and hippocampus by 10% to 29%. However, in dAMPH users the CBF response was blunted in most brain areas studied, only decreasing in the hippocampus and orbitofrontal cortex. When comparing groups, CBF response was found to be significantly different in the thalamus with a decrease for healthy controls and a blunted response in dAMPH users. Collectively, our findings of a blunted hemodynamic response in monoaminergic regions, in combination with indications for lower striatal DAT binding and poorer behavioral measures are likely to represent DAergic dysfunction in dAMPH users, although NAergic dysfunction may also play a role.

Receiver-Operating-Characteristic Analysis of an Automated Program for Analyzing Striatal Uptake of 123I-Ioflupane SPECT Images: Calibration Using Visual Reads

A fully automated objective striatal analysis (OSA) program that quantitates dopamine transporter uptake in subjects with suspected Parkinson's disease was applied to images from clinical (123)I-ioflupane studies. The striatal binding ratios or alternatively the specific binding ratio (SBR) of the lowest putamen uptake was computed, and receiver-operating-characteristic (ROC) analysis was applied to 94 subjects to determine the best discriminator using this quantitative method. Ninety-four (123)I-ioflupane SPECT scans were analyzed from patients referred to our clinical imaging department and were reconstructed using the manufacturer-supplied reconstruction and filtering parameters for the radiotracer. Three trained readers conducted independent visual interpretations and reported each case as either normal or showing dopaminergic deficit (abnormal). The same images were analyzed using the OSA software, which locates the striatal and occipital structures and places regions of interest on the caudate and putamen. Additionally, the OSA places a region of interest on the occipital region that is used to calculate the background-subtracted SBR. The lower SBR of the 2 putamen regions was taken as the quantitative report. The 33 normal (bilateral comma-shaped striata) and 61 abnormal (unilateral or bilateral dopaminergic deficit) studies were analyzed to generate ROC curves. Twenty-nine of the scans were interpreted as normal and 59 as abnormal by all 3 readers. For 12 scans, the 3 readers did not unanimously agree in their interpretations (discordant). The ROC analysis, which used the visual-majority-consensus interpretation from the readers as the gold standard, yielded an area under the curve of 0.958 when using 1.08 as the threshold SBR for the lowest putamen. The sensitivity and specificity of the automated quantitative analysis were 95% and 89%, respectively. The OSA program delivers SBR quantitative values that have a high sensitivity and specificity, compared with visual interpretations by trained nuclear medicine readers. Such a program could be a helpful aid for readers not yet experienced with (123)I-ioflupane SPECT images and if further adapted and validated may be useful to assess disease progression during pharmaceutical testing of therapies.

Interobserver variability, and visual and quantitative parameters of 123I-FP-CIT SPECT (DaTSCAN) studies

To evaluate the degree of interobserver agreement in the visual interpretation of (123)I-FP-CIT studies and to investigate for potential associations between visual and semi-quantitative parameters. Eighty-nine (123)I-FP-CIT studies were blindly reviewed by 3 independent observers: a consultant, a resident doctor and a radiographer. They classified every study as either "normal" or "abnormal" and assigned visual (123)I-FP-CIT uptake scores (2: normal, 1: reduced and 0: no uptake) in basal ganglia nuclei (right and left putamina and caudate nuclei) on every scan. Striatal (123)I-FP-CIT binding ratios were calculated using crescent-ROI software. The interobserver agreement for the interpretation of studies and for visual score assignment was evaluated by means of κ statistics. We investigated for associations of binding ratios with visual scores and clinical parameters; patients' clinical diagnoses served as the reference standard. There was excellent interobserver agreement (κ 0.89-0.93) in classifying studies as "normal" or "abnormal" and fine agreement in assignment of visual scores (κ 0.71-0.80 for putamina and 0.50-0.79 for caudate nuclei). Nuclei with scores of 1 and 0 showed significantly reduced binding ratios (about 30 and 50%, respectively) compared with the nuclei scored as 2. ROC analysis indicated the optimal cutoff point of striatal binding ratio at 3.8 (sensitivity 98.5%, specificity 95%) for the detection of parkinsonian syndromes. Striatal binding ratios were negatively associated with age in normal subjects and disease duration in Parkinson's disease patients. Visual interpretation of (123)I-FP-CIT studies showed very good interobserver agreement. We found significant associations among visual, semi-quantitative and clinical parameters.

Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson's disease

The aim of this study was to investigate whether visual assessment of (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan ((123)I-FP-CIT) single photon emission computed tomography (SPECT) in addition to quantitative analyses can help to differentiate idiopathic Parkinson's disease (PD) from atypical parkinsonian syndromes (APS). From a consecutive series of patients examined with (123)I-FP-CIT SPECT (n = 190) over a three-year period we identified 165 patients with a clinical diagnosis of PD (n = 120) or APS (n = 45). (123)I-FP-CIT SPECT results were analysed visually and quantitatively and compared for PD and APS and for the subgroup of patients with early PD and APS (disease duration <5 years). According to predefined visual patterns of dopaminergic degeneration the results were graded as normal (grade 5) or abnormal (grade 1-4), distinguishing a posterior-anterior degeneration pattern ("egg shape") from a global and severe degeneration pattern ("burst striatum"). Visual assessment of (123)I-FP-CIT SPECT showed significant different dopaminergic degeneration patterns for PD and APS patients. A grade 1 ("burst striatum") degeneration pattern was predominantly associated with APS patients. In contrast to that, a grade 2 (egg shape) degeneration pattern was the characteristic finding in PD patients. In a subgroup of patients with early disease, visual assessment with identification of the burst striatum degeneration pattern provided 90% positive predictive value and 99% specificity for the diagnosis of APS. Quantitative analysis of striatal binding ratios failed to depict these different degeneration patterns in PD and APS patients. Visual assessment of the pattern of dopaminergic loss in (123)I-FP-CIT SPECT shows different patterns of dopaminergic degeneration for PD and APS patients. Therefore, it could provide valuable information to distinguish APS from PD patients, especially in early stages of disease. Within the first 5 years of disease, the occurrence of a burst striatum degeneration pattern has a high positive predictive value of APS.

Subclinical nigrostriatal dopaminergic denervation in the cerebellar subtype of multiple system atrophy (MSA-C)

Nigrostriatal involvement is considered an additional feature in the new consensus criteria for the diagnosis of the cerebellar variant of multiple system atrophy (MSA-C). However, so far, only a few studies, which include a relative small number of patients, give support to this criterion. Our objective was to assess nigrostriatal dopaminergic innervation in patients with MSA-C without parkinsonism by use of dopamine transporter single photon emission computed tomography (DAT SPECT). Thirteen patients that fulfilled criteria for possible or probable MSA-C and presented no parkinsonian signs, and 12 age-matched healthy controls underwent ((123)I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([(123)I]FP-CIT) SPECT. Patients were also evaluated through the Unified Multiple System Atrophy Rating Scale (UMSARS) and brain magnetic resonance imaging (MRI). The mean duration of the cerebellar syndrome was 3.8 ± 1.7 years. DAT SPECT showed a significant decrease of striatal [(123)I]FP-CIT uptake ratios in patients (p < 0.001). Radiotracer uptake reduction was 21% in the entire striatum, 19% in putamen, and 24% in caudate nuclei. Striatal binding ratios were within the normal range in 3 patients. We did not find correlation between striatal uptake and disease duration, age of patients, UMSARS-II score, and pontine diameter. [(123)I]FP-CIT SPECT shows that most but not all MSA-C patients without parkinsonism have subclinical nigrostriatal dopaminergic denervation which is not related to disease duration, cerebellar dysfunction, or pontine atrophy.

MRI-Guided Region-of-Interest Delineation Is Comparable to Manual Delineation in Dopamine Transporter SPECT Quantification in Patients: A Reproducibility Study

A particularly sensitive step in the quantification of SPECT images of the dopamine transporter (DAT) is a correct delineation of the region of interest (ROI). In this study, we primarily compared the reproducibility of the following different approaches for ROI delineation in SPECT images of the DAT: the use of manual delineation (MD) on high-count striatal slides directly on the SPECT image, ROI delineation based on individual MR images (MRD), and oversized striatal ROIs-that is, the striatal volume of interest (SVI), as described previously. We also assessed the ability of the different approaches to identify striatal pathology in patients with parkinsonism. Eight patients with highly variable reductions in cerebral DAT availability were SPECT-scanned twice with (123)I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4'-methylphenyl) nortropane bolus infusion setup and once with an MRI scanner. For SPECT/MRI coregistration, we used external fiducial markers visible on both MRI and SPECT. With the MD and MRD methods, the outcome parameters for DAT availability were the binding potentials and the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BP(ND)). For the SVI method, the outcome parameter was the specific binding ratio (SBR). No statistically significant difference in striatal BP(ND) intraobserver reproducibility was seen among any of the 3 methods. The intraobserver reproducibility average +/- SD for MD was 7.0% +/- 4.1%; for MRD, 5.7% +/- 5.4%; and for SVI, 6.7% +/- 6.0%. Mean intrasubject variability, as determined from the test-retest scans, did not differ with the 3 delineation methods used. The average (+/-SD) intrasubject variability of striatal BP(ND) was 11.9% +/- 10.0% with MD and 14.6% +/- 15.3% with MRD. With the SVI method, the intrasubject variability of striatal specific binding ratio was 10.0% +/- 10.2%. BP(ND) values obtained with the MD and MRD methods were similar (paired t test, P > 0.4). In patients with reduced striatal DAT binding, the reproducibility of the outcome from ROI MD is comparable to both that obtained by delineation of ROI on individual MR images, followed by coregistration to the SPECT image, and that obtained with the SVI-based approach.

Reduced striatal D2 receptor binding in myoclonus–dystonia

To study striatal dopamine D(2) receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus-dystonia (M-D). Fifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using (123)I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas. Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects. Our findings are consistent with the theory of reduced dopamine D(2) receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.