Dopamine Transporter Single-photon Emission Computed Tomography Research Articles

Dopamine transporter single-photon emission computed tomography-derived radiomics signature for detecting Parkinson’s disease

BackgroundWe hypothesised that the radiomics signature, which includes texture information of dopamine transporter single-photon emission computed tomography (DAT-SPECT) images for Parkinson’s disease (PD), may assist semi-quantitative indices. Herein, we constructed a radiomics signature using DAT-SPECT-derived radiomics features that effectively discriminated PD from healthy individuals and evaluated its classification performance.ResultsWe analysed 413 cases of both normal control (NC, n = 101) and PD (n = 312) groups from the Parkinson’s Progression Markers Initiative database. Data were divided into the training and two test datasets with different SPECT manufacturers. DAT-SPECT images were spatially normalised to the Montreal Neurologic Institute space. We calculated 930 radiomics features, including intensity- and texture-based features in the caudate, putamen, and pallidum volumes of interest. The striatum uptake ratios (SURs) of the caudate, putamen, and pallidum were also calculated as conventional semi-quantification indices. The least absolute shrinkage and selection operator was used for feature selection and construction of the radiomics signature. The four classification models were constructed using a radiomics signature and/or semi-quantitative indicator. Furthermore, we compared the classification performance of the semi-quantitative indicator alone and the combination with the radiomics signature for the classification models. The receiver operating characteristics (ROC) analysis was used to evaluate the classification performance. The classification performance of SURputamen was higher than that of other semi-quantitative indicators. The radiomics signature resulted in a slightly increased area under the ROC curve (AUC) compared to SURputamen in each test dataset. When combined with SURputamen and radiomics signature, all classification models showed slightly higher AUCs than that of SURputamen alone.ConclusionWe constructed a DAT-SPECT image-derived radiomics signature. Performance analysis showed that the current radiomics signature would be helpful for the diagnosis of PD and has the potential to provide robust diagnostic performance.

Striatal Dopaminergic Depletion Pattern Reflects Pathological Brain Perfusion Changes in Lewy Body Diseases

PurposeIn Lewy body diseases (LBD), various symptoms occur depending on the distribution of Lewy body in the brain, and the findings of brain perfusion and dopamine transporter single-photon emission computed tomography (DAT-SPECT) also change accordingly. We aimed to evaluate the correlation between brain perfusion SPECT and quantitative indices calculated from DAT-SPECT in patients with LBD.ProceduresWe retrospectively enrolled 35 patients with LBD who underwent brain perfusion SPECT with N-isopropyl-p-[123I] iodoamphetamine and DAT-SPECT with 123I-ioflupane. Mini-mental state examination (MMSE) data were also collected from 19 patients. Quantitative indices (specific binding ratio [SBR], putamen-to-caudate ratio [PCR], and caudate-to-putamen ratio [CPR]) were calculated using DAT-SPECT. These data were analysed by the statistical parametric mapping procedure.ResultsIn patients with LBD, decreased PCR index correlated with hypoperfusion in the brainstem (medulla oblongata and midbrain) (uncorrected p < 0.001, k > 100), while decreased CPR index correlated with hypoperfusion in the right temporoparietal cortex (family-wise error corrected p < 0.05), right precuneus (uncorrected p < 0.001, k > 100), and bilateral temporal cortex (uncorrected p < 0.001, k > 100). However, there was no significant correlation between decreased SBR index and brain perfusion. Additionally, the MMSE score was correlated with hypoperfusion in the left temporoparietal cortex (uncorrected p < 0.001).ConclusionsThis study suggests that regional changes in striatal 123I-ioflupane accumulation on DAT-SPECT are related to brain perfusion changes in patients with LBD.

Dopamine Transporter Imaging for Frontotemporal Lobar Degeneration With Motor Neuron Disease.

IntroductionFrontotemporal lobar degeneration (FTLD) is a clinical syndrome with pathological heterogeneity, including Pick’s disease and trans-activating response region (TAR) DNA-binding protein with a molecular mass of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). A previous study reported abnormal findings on dopamine transporter (DAT) imaging in 30% of patients with frontotemporal dementia (FTD) in FTLD. However, the previous study did not consider the pathological heterogeneity of FTD regarding the pathomechanism leading to abnormal DAT findings. Recently, abnormal DAT findings were reported in two patients with FTLD with motor neuron disease (MND), of which FTLD-TDP type B was the most common pathological presentation. This study investigated the DAT findings of patients with a final diagnosis of FTLD-MND to determine the frequency of occurrence of DAT abnormalities in FTLD-MND.MethodsTwenty patients with FTLD who underwent DAT single photon emission computed tomography (DAT-SPECT) were screened, and six patients with a final diagnosis of FTLD-MND were ultimately included. The patients’ DAT-SPECT findings were analyzed visually and quantitatively. Neuronal loss and astrogliosis in brain regions (substantia nigra, caudate, and putamen) that could possibly affect DAT findings were evaluated in the three pathologically confirmed cases.ResultAll six patients with FTLD-MND showed abnormal visual DAT-SPECT findings. In addition, in a quantitative assessment, the specific binding ratio in the striatum calculated by the Southampton method was below the lower limit of the 95% prediction interval of the healthy controls by age in all the present cases. Interestingly, three of the six patients showed abnormal findings on DAT-SPECT more than half a year before the onset of MND. Neuronal loss and astrogliosis in brain regions that may affect DAT findings were observed in three pathologically confirmed cases.ConclusionDopamine transporter single photon emission computed tomography revealed abnormal findings in patients with FTLD-MND, which may manifest even before the onset of MND symptoms. We believe that the possibility of future development of MND should be considered if DAT-SPECT shows abnormal findings in FTLD.

Increased Transferrin Sialylation Predicts Phenoconversion in Isolated REM Sleep Behavior Disorder.

BackgroundSialic acid–protein interactions are involved in regulating central nervous system immunity; therefore, derangements in sialylation could be involved in neurodegeneration.ObjectivesWe evaluate the differences in serum transferrin sialylation in prodromal and early‐stage Parkinson's disease (PD), its relation to substantia nigra degeneration, and the risk of phenoconversion to manifest disease.MethodsSixty treatment‐naive PD patients; 72 polysomnography‐confirmed isolated rapid eye movement sleep behavior disorder (iRBD) patients, that is, patients with prodromal synucleinopathy; and 46 healthy volunteers aged ≥45 years and drinking ≤60 standard drinks per month were included. The proportion of serum low‐sialylated, carbohydrate‐deficient transferrin (CDT) isoforms was assessed using high‐performance liquid chromatography, and the values were adjusted for alcohol intake (CDTadj). Dopamine transporter single‐photon emission computed tomography (DaT‐SPECT) imaging was performed. In iRBD, phenoconversion risk of DaT‐SPECT and CDTadj was evaluated using Cox regression adjusted for age and sex.ResultsMedian CDTadj was lower in PD (1.1 [interquartile range: 1.0–1.3]%) compared to controls (1.2 [1.1–1.6]%) (P = 0.001). In iRBD, median CDTadj was lower in subjects with abnormal (1.1 [0.9–1.3]%) than normal (1.3 [1.2–1.6]%) DaT‐SPECT (P = 0.005). After a median 44‐month follow‐up, 20% of iRBD patients progressed to a manifest disease. Although iRBD converters and nonconverters did not significantly differ in CDTadj levels (P = 0.189), low CDTadj increased the risk of phenoconversion with hazard ratio 3.2 (P = 0.045) but did not refine the phenoconversion risk associated with abnormal DaT‐SPECT yielding hazard ratio 15.8 (P < 0.001).ConclusionsDecreased serum CDTadj is associated with substantia nigra degeneration in synucleinopathies. iRBD patients with low CDTadj are more likely to phenoconvert to manifest disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Practical Application of DaTQUANT with Optimal Threshold for Diagnostic Accuracy of Dopamine Transporter SPECT.

Evaluation of Parkinsonian Syndromes (PS) with Ioflupane iodine-123 dopamine transporter single photon emission computed tomography (DaT-SPECT), in conjunction with history and clinical examination, aids in diagnosis. FDA-approved, semi-quantitative software, DaTQUANTTM (GE Healthcare, Chicago, IL, USA) is available to assist in interpretation. This study aims to evaluate the optimal variables and thresholds of DaTQUANT to yield the optimal diagnostic accuracy. It is a retrospective review with three different patient populations. DaT-SPECT images from all three study groups were evaluated using DaTQUANTTM software, and both single and multi-variable logistic regression were used to model PS status. The optimal models were chosen via accuracy, sensitivity, and specificity, then evaluated on the other study groups. Among single variable models, the posterior putamen yielded the highest accuracy (84% to 95%), while balancing sensitivity and specificity. Multi-variable models did not substantially improve the accuracy. When the optimal single variable models for each group were used to evaluate the remaining two groups, comparable results were achieved. In typical utilization of DaT-SPECT for differentiation between nigrostriatal degenerative disease (NSDD) and non-NSDD, the posterior putamen was the single variable that yielded the highest accuracy across three different patient populations. The posterior putamen’s recommended thresholds for DaTQUANT are SBR ≤ 1.0, z-score of ≤−1.8 and percent deviation ≤ −0.34.

Dysprosody in Isolated REM Sleep Behavior Disorder with Impaired Olfaction but Intact Nigrostriatal Pathway.

Impairments of olfactory and speech function are likely early prodromal symptoms of α-synucleinopathy. The aim of this study is to assess whether dysprosody is present in isolated rapid eye movement sleep behavior disorder (iRBD) with hyposmia/anosmia and a normal nigrostriatal system. Pitch variability during speech was investigated in 17 iRBD subjects with normal olfactory function (iRBD-NOF), 30 iRBD subjects with abnormal olfactory function (iRBD-AOF), and 50 healthy controls. iRBD subjects were evaluated using the University of Pennsylvania Smell Identification Test and [123I]-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane dopamine transporter single-photon emission computed tomography (DAT-SPECT). All iRBD subjects completed the 24-month follow-up with DAT-SPECT, speech, and olfactory testing. At baseline, only iRBD-AOF showed monopitch when compared to iRBD-NOF (P=0.04) and controls (P=0.03), with no difference between iRBD-NOF and controls (P=1). At follow-up, dysprosody progressed only in iRBD-AOF with abnormal DAT-SPECT (P=0.03). Prosody is impaired in hyposmic but not in normosmic iRBD subjects before the nigrostriatal dopaminergic transmission is affected (Braak stage 2). © 2021 International Parkinson and Movement Disorder Society.

Stratification Tools for Disease-Modifying Trials in Prodromal Synucleinopathy.

ABSTRACTBackgroundDopamine transporter single photon‐emission computed tomography (DAT‐SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye movement (REM)‐sleep behavior disorder (iRBD). However, it might be used as a second‐line stratification tool in clinical trials, because it is expensive and mini‐invasive.ObjectiveAim of the study is to investigate whether other cost‐effective and non‐invasive biomarkers may be proposed as first‐line stratification tools.MethodsForty‐seven consecutive iRBD patients (68.53 ± 7.16 years, 40 males) underwent baseline clinical and neuropsychological assessment, olfaction test, resting electroencephalogram (EEG), and DAT‐SPECT. All patients underwent 6 month‐based clinical follow‐up to investigate the emergence of parkinsonism and/or dementia. Survival analysis and Cox regression were used to estimate conversion risk.ResultsSeventeen patients developed an overt synucleinopathy (eight Parkinsonism and nine dementia) 32.8 ± 22 months after diagnosis. The strongest risk factors were putamen specific to non‐displaceable binding ratio (SBR) (hazard ratio [HR], 7.3), attention/working memory cognitive function (NPS‐AT/WM) (HR, 5.9), EEG occipital mean frequency (HR, 2.7) and clinical motor assessment (HR, 2.3). On multivariate Cox‐regression analysis, only putamen SBR and NPS‐AT/WM significantly contributed to the model (HR, 6.2, 95% confidence interval [CI], 1.9–19.8). At post‐hoc analysis, the trail‐making test B (TMT‐B) was the single most efficient first‐line stratification tool that allowed to reduce the number of eligible subjects to 76.6% (sensitivity 1, specificity 0.37). Combining TMT‐B and DAT‐SPECT further reduced the sample to 66% (sensitivity 0.88, specificity 0.47).ConclusionThe TMT‐B seems to be a cost‐effective and efficient first‐line screening tool, to be used to select patients that deserve DAT‐SPECT as second‐line screening tool for disease‐modifying clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Serial DaT-SPECT imaging in asymptomatic carriers of LRRK2 G2019S mutation: 8 years' follow-up.

Carriers of the G2019S mutation of LRRK2 provide a great opportunity to investigate the premotor stages of Parkinson's disease (PD). We have studied by serial clinical and dopamine transporter single photon emission computed tomography (DaT-SPECT) evaluations a cohort of asymptomatic carriers of the LRRK2-G2019S mutation in order to evaluate the usefulness of these tools as biomarkers. Here we report the results of the extended follow-up of this cohort at 8years. Seventeen participants, of the 25 available from the 4-year evaluation, completed the 8-year assessment. UPDRS-III, UPSIT test and DaT-SPECT imaging (123 I-ioflupane) were performed. We used repeated-measures linear mixed effects models to examine the changes in DaT binding over time. Three carriers had converted to PD at 4 years. One additional carrier converted at 8 years. PD-converters had lower striatal DaT binding at baseline than non-converters. There was a significant decline of DaT binding over time, with a mean annual rate of 3.5%, with somewhat inter-individual and intra-individual variability and comparable between PD-converters and non-converters. No carrier with DAT binding ratio above an undefined threshold between 0.5 and 0.8 developed PD symptoms. The age-adjusted UPSIT score did not change significantly over time. The rate of conversion to PD at 8years in this cohort aged ~58years at baseline was 16%. The observed decline of DaT binding over time and its association with the phenotype render DaT-SPECT a potentially useful tool for monitoring the premotor stage of the disease, although at the individual level its ability to predict phenoconversion is limited.

Patients with REM sleep behavior disorder have higher serum levels of allantoin

IntroductionRapid eye movement (REM) sleep behavior disorder (RBD) is associated with an increased risk of developing Parkinson's disease (PD). Low uric acid (UA) levels are associated with the risk of development and progression of PD. Allantoin is the major oxidation product of UA and is considered as a biomarker of oxidative stress. We aimed to compare serum levels of UA, allantoin, and allantoin/UA ratio in RBD patients with those in healthy controls, and to examine their associations with clinical severity. MethodsWe evaluated serum levels of UA, allantoin, and allantoin/UA ratio in 38 RBD patients (one female, mean age 66.8 (SD 6.3) years) and in 47 controls (four females, 66.8 (7.6) years). All RBD patients were assessed according to an examination protocol, which included structured interview, Montreal Cognitive Assessment (MoCA), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and dopamine transporter single-photon emission computed tomography (DAT-SPECT). The lower putaminal binding ratio from both hemispheres was used for analysis. ResultsMean serum allantoin concentration and allantoin/UA ratio were significantly increased in the RBD group compared to controls (2.6 (1.8) vs. 1.4 (0.7) μmol/l, p = 0.0004, and 0.008 (0.004) vs. 0.004 (0.002), p < 0.0001, respectively). There were no significant differences in UA levels between the two groups. No significant associations between any biochemical parameter and RBD duration, putaminal binding ratio on DAT-SPECT, MDS-UPDRS, or MoCA score were found. ConclusionSerum allantoin and allantoin/UA ratio are increased in RBD patients in comparison to controls, which may reflect increased systemic oxidative stress in prodromal synucleinopathy.

Dopamine transporter SPECT imaging in Parkinson’s disease and parkinsonian disorders

The dopamine transporter (DAT) imaging provides an objective tool for the assessment of dopaminergic function of presynaptic terminals which is valuable for the differential diagnosis of parkinsonian disorders related to a striatal dopaminergic deficiency from movement disorders not related a striatal dopaminergic deficiency. DAT imaging with single-photon emission computed tomography (SPECT) can be used to confirm or exclude a diagnosis of dopamine deficient parkinsonism in cases where the diagnosis is unclear. It can also detect the dopaminergic dysfunction in presymptomatic subjects at risk for Parkinson’s disease (PD) since the reduced radiotracer binding to DATs in striatum is already present in the prodromal stage of PD. This review covers the rationale of using DAT SPECT imaging in the diagnosis of PD and other parkinsonian disorders, specifically focusing on the practical aspects of imaging and routine clinical indications.

Systematic video-analysis of motor events during REM sleep in idiopathic REM sleep behavior disorder, follow-up and DAT-SPECT

Abnormal motor manifestations in REM sleep are the most visible feature of idiopathic REM sleep behavior disorder (iRBD), which precedes the overt alpha-synucleinopathy. The aim of this study was to perform a systematic visual analysis of the motor events (ME) captured during video-polysomnography, and clarify their relation to the disease severity.Thirty-four iRBD patients (5 women, 29 men; age 67.7 ± 7.2) with a mean follow-up duration 2.9 ± 1.1 years. and 33 controls (10 women, 23 men; age 61.5 ± 8.2) were examined. The ME captured during REM sleep were classified into four categories, previously defined by Frauscher et al. according to clinical severity: minor/simple jerks, major, complex and violent.An average frequency of 110.8 ± 75.2 ME per hour were identified in iRBD, 7.5 ± 11.6 in the controls (p < 0.001). Of these ME, 68.4% were classified as minor/simple jerks, 9.3% as major, 21.7% as complex and 0.7% as violent. The ME frequency was negatively associated with tracer binding on dopamine transporter single-photon emission computed tomography (DAT-SPECT); the association was stronger for caudate nucleus compared to putamen. During follow-up seven patients (24.1%) phenoconverted, yielding a yearly phenoconversion rate 8.3%. Violent ME were associated with increased hazard ratio for phenoconversion in frequency (p = 0.012) and total duration (p = 0.007).Patients with higher amounts of violent ME had a greater risk of phenoconversion; therefore, their role as a predictor should be considered. Additionally, ME were associated with nigrostriatal degeneration, according to DAT-SPECT. These findings indicate that the degree of the clinical severity of motor manifestations in iRBD reflects the severity of the disease.

A diagnostic strategy for Parkinsonian syndromes using quantitative indices of DAT SPECT and MIBG scintigraphy: an investigation using the classification and regression tree analysis

PurposeWe aimed to evaluate the diagnostic performances of quantitative indices obtained from dopamine transporter (DAT) single-photon emission computed tomography (SPECT) and 123I-metaiodobenzylguanidine (MIBG) scintigraphy for Parkinsonian syndromes (PS) using the classification and regression tree (CART) analysis.MethodsWe retrospectively enrolled 216 patients with or without PS, including 80 without PS (NPS) and 136 with PS [90 Parkinson’s disease (PD), 21 dementia with Lewy bodies (DLB), 16 progressive supranuclear palsy (PSP), and 9 multiple system atrophy (MSA). The striatal binding ratio (SBR), putamen-to-caudate ratio (PCR), and asymmetry index (AI) were calculated using DAT SPECT. The heart-to-mediastinum uptake ratio (H/M) based on the early (H/M [Early]) and delayed (H/M [Delay]) images and cardiac washout rate (WR) were calculated from MIBG scintigraphy. The CART analysis was used to establish a diagnostic decision tree model for differentiating PS based on these quantitative indices.ResultsThe sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 87.5, 96.3, 93.3, 92.9, and 93.1 for NPS; 91.1, 78.6, 75.2, 92.5, and 83.8 for PD; 57.1, 95.9, 60.0, 95.4, and 92.1 for DLB; and 50.0, 98.0, 66.7, 96.1, and 94.4 for PSP, respectively. The PCR, WR, H/M (Delay), and SBR indices played important roles in the optimal decision tree model, and their feature importance was 0.61, 0.22, 0.11, and 0.05, respectively.ConclusionThe quantitative indices showed high diagnostic performances in differentiating NPS, PD, DLB, and PSP, but not MSA. Our findings provide useful guidance on how to apply these quantitative indices in clinical practice.

Using Artificial Neural Network to Discriminate Parkinson's Disease from Other Parkinsonisms by Focusing on Putamen of Dopamine Transporter SPECT Images.

Background: The challenge of differentiating, at an early stage, Parkinson’s disease from parkinsonism caused by other disorders remains unsolved. We proposed using an artificial neural network (ANN) to process images of dopamine transporter single-photon emission computed tomography (DAT-SPECT). Methods: Abnormal DAT-SPECT images of subjects with Parkinson’s disease and parkinsonism caused by other disorders were divided into training and test sets. Striatal regions of the images were segmented by using an active contour model and were used as the data to perform transfer learning on a pre-trained ANN to discriminate Parkinson’s disease from parkinsonism caused by other disorders. A support vector machine trained using parameters of semi-quantitative measurements including specific binding ratio and asymmetry index was used for comparison. Results: The predictive accuracy of the ANN classifier (86%) was higher than that of the support vector machine classifier (68%). The sensitivity and specificity of the ANN classifier in predicting Parkinson’s disease were 81.8% and 88.6%, respectively. Conclusions: The ANN classifier outperformed classical biomarkers in differentiating Parkinson’s disease from parkinsonism caused by other disorders. This classifier can be readily included into standalone computer software for clinical application.

Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson's Disease.

Orthostatic hypotension (OH) at an early stage of Parkinson's disease (PD) predicts poor prognosis, which may suggest degeneration of dopaminergic neurons affects sympathetic function, causing OH. We tested the hypothesis that striatal dopaminergic depletion is associated with OH in PD. Out of 99 patients with newly diagnosed untreated PD, 81 patients were enrolled according to our selection criteria. All patients underwent head-up tilt-table testing and striatal 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT data. The association between hemodynamic changes and 123I-FP-CIT uptake was examined. 123I-FP-CIT uptake in the putamen, especially the anterior part and left side, was related not only to motor severity but also to OH. Change in systolic blood pressure correlated negatively with 123I-FP-CIT uptake in bilateral anterior putamen (left: p < 0.01, right: p < 0.05) and left posterior putamen (p < 0.05). Patients with OH had more severe dopamine depletion in left anterior (p = 0.008) and posterior (p = 0.007) putamen at a similar motor severity than did patients without OH even though both groups have similar baseline characteristics. An analysis of asymmetry index showed patients with OH had symmetrically decreased dopamine levels in anterior putamen when compared to those without OH (p = 0.024). OH is closely related to striatal dopamine depletion in PD. This relation may help to account for the prognostic value of OH.

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 the size of the normal database on the performance of the specific binding ratio in dopamine transporter SPECT

BackgroundThis study investigated the impact of the size of the normal database on the classification performance of the specific binding ratio (SBR) in dopamine transporter (DAT) SPECT with [123I]FP-CIT in different settings.MethodsThe first subject sample comprised 645 subjects from the Parkinson’s Progression Marker Initiative (PPMI), 207 healthy controls (HC), and 438 Parkinson’s disease (PD) patients. The second sample comprised 372 patients from clinical routine patient care, 186 with non-neurodegenerative parkinsonian syndrome (PS) and 186 with neurodegenerative PS. Single-photon emission computed tomography (SPECT) images of the clinical sample were reconstructed with two different reconstruction algorithms (filtered backprojection, iterative ordered subsets expectation maximization (OSEM) reconstruction with resolution recovery). The putaminal specific binding ratio (SBR) was computed using an anatomical region of interest (ROI) predefined in standard (MNI) space in the Automated Anatomic Labeling (AAL) atlas or using hottest voxels (HV) analysis in large predefined ROIs. SBR values were transformed to z-scores using mean and standard deviation of the SBR in a normal database of varying sizes (n = 5, 10, 15,…, 50) randomly selected from the HC subjects (PPMI sample) or the patients with non-neurodegenerative PS (clinical sample). Accuracy, sensitivity, and specificity for identifying patients with PD or neurodegenerative PS were determined as performance measures using a predefined fixed cutoff on the z-score. This was repeated for 10,000 randomly selected normal databases, separately for each size of the normal database. Mean and 5th percentile of the performance measures over the 10,000 realizations were computed. Accuracy, sensitivity, and specificity when using the whole set of HC or non-neurodegenerative PS subjects as normal database were used as benchmark.ResultsMean loss of accuracy of the putamen SBR z-score was below 1% when the normal database included at least 15 subjects, independent of subject sample (PPMI or clinical), reconstruction method (filtered backprojection or OSEM), and ROI method (AAL or HV). However, the variability of the accuracy of the putamen SBR z-score decreased monotonically with increasing size of normal database and was still considerable at size 15. In order to achieve less than 5% “maximum” loss of accuracy (defined by the 5th percentile) in all settings required at least 25 to 30 subjects in the normal database. Reduction of mean and “maximum” loss of accuracy of the putamen SBR z-score by further increasing the size of the normal database was very small beyond size 40.ConclusionsThe results of this study suggest that 25 to 30 is the minimum size of the normal database to reliably achieve good performance of semi-quantitative analysis in dopamine transporter (DAT) SPECT, independent of the algorithm used for image reconstruction and the ROI method used to estimate the putaminal SBR.

A diagnostic strategy for Lewy body disease using DAT-SPECT, MIBG and Combined index.

The functional imaging methods widely used for the diagnosis of Lewy body disease (LBD) are 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropan (FP-CIT) with dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-iodobenzylguanidine (MIBG) myocardial scintigraphy. The aim of this study was to determine whether DAT-SPECT or 123I-MIBG myocardial scintigraphy should be examined first and to evaluate whether the combined use of DAT-SPECT and MIBG myocardial scintigraphy is superior to using either modality alone for diagnosing suspected LBD. In this retrospective study, a total of 117 patients suspected of having LBD underwent DAT-SPECT imaging followed by MIBG myocardial scintigraphy. The delayed heart-to-mediastinum (H/M) ratio of MIBG scintigraphy, and the specific binding ratio (SBR) of DAT-SPECT imaging, and Combined index (defined as SBR mean×H/M in the delayed phase) were used as semi-quantitative measures. The diagnostic ability was evaluated using these indexes. The sensitivity, specificity, and accuracy of diagnosing Lewy body disease were 59.6%, 71.4%, and 67.5% by SBR mean of DAT-SPECT, 85.1%, 91.4%, and 88.9% by delayed H/M ratio of MIBG myocardial scintigraphy, 76.6%, 74.3%, and 75.2% by Combined index, respectively. In the diagnosis of LBD, DAT-SPECT, MIBG myocardial scintigraphy, and Combined index may be reliable indices. In particular, MIBG myocardial scintigraphy was the specific modality for LBD diagnosis. Understanding the effectiveness and limits of DAT-SPECT and MIBG myocardial scintigraphy and using both properly will lead to a more accurate diagnosis and better treatment.

Comparative study of the substantia nigra echogenicity and 123I-Ioflupane SPECT in patients with synucleinopathies with and without REM sleep behavior disorder

ObjectivesHyperechogenicity of the substantia nigra (SN) and abnormal dopamine transporter-single-photon emission computed tomography (DAT-SPECT) are biomarkers commonly used in the assessment of prodromal synucleinopathy. Our goals were as follows: (1) to compare echogenicity of SN in idiopathic rapid eye movement (REM) behavior disorder (iRBD), Parkinson's disease (PD) without RBD (PD-noRBD), PD with RBD (PD + RBD), and control subjects; and (2) to examine association between SN degeneration assessed by DAT-SPECT and SN echogenicity. Patients/methodsA total of 61 subjects with confirmed iRBD were examined using Movement Disorders Society-unified PD rating scale (MDS-UPDRS), TCS (transcranial sonography) and DAT-SPECT. The results were compared with 44 patients with PD (25% PD + RBD) and with 120 age-matched healthy subjects. Results and conclusionThe abnormal SN area was found in 75.5% PD, 23% iRBD and 7.3% controls. Median SN echogenicity area in PD (0.27 ± 0.22 cm2) was higher compared to iRBD (0.07 ± 0.07 cm2; p < 0.0001) and controls (0.05 ± 0.03 cm2; p < 0.0001). SN echogenicity in PD + RBD was not significantly different from PD-noRBD (0.30 vs. 0.22, p = 0.15).Abnormal DAT-SPECT was found in 16 iRBD (25.4%) and 44 PD subjects (100%). No correlation between the larger SN area and corresponding putaminal binding index was found in iRBD (r = −0.13, p = 0.29), nor in PD (r = −0.19, p = 0.22).The results of our study showed that: (1) SN echogenicity area in iRBD was higher compared to controls, but the hyperechogenicity was present only in a minority of iRBD patients; (2) SN echogenicity and DAT-SPECT binding index did not correlate in either group; and (3) SN echogenicity does not differ between PD with/without RBD.

Relations of non-motor symptoms and dopamine transporter binding in REM sleep behavior disorder

The aim of this study was to evaluate associations of motor and non-motor symptoms with dopamine transporter binding in prodromal stage of synucleinopathies. We examined 74 patients with idiopathic REM sleep behavior disorder (RBD), which is a prodromal synucleinopathy, and 39 controls using Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test (UPSIT), Farnsworth-Munsell 100 hue test, orthostatic test, Scales for Outcomes in PD-Autonomic, Beck depression inventory-II, State-Trait Anxiety Inventory, and video-polysomnography. Electromyographic muscle activity during REM sleep was quantified according to Sleep Innsbruck-Barcelona criteria. In 65 patients, dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging was performed, putaminal binding ratio was calculated and scans were classified as normal, borderline, or abnormal. Compared to controls, RBD patients had significantly more severe scores in all examined tests. Patients with abnormal DAT-SPECT had higher MDS-UPDRS motor score (p = 0.006) and higher prevalence of orthostatic hypotension (p = 0.008). Putaminal binding ratio was positively associated with UPSIT score (p = 0.03) and negatively associated with tonic (p = 0.003) and phasic (p = 0.01) muscle activity during REM sleep. These associations likely reflect simultaneous advancement of underlying pathology in substantia nigra and susceptible brainstem and olfactory nuclei in prodromal synucleinopathy.

Artificial Neural Network-Based Prediction of Outcome in Parkinson's Disease Patients Using DaTscan SPECT Imaging Features.

Quantitative analysis of dopamine transporter (DAT) single-photon emission computed tomography (SPECT) images can enhance diagnostic confidence and improve their potential as a biomarker to monitor the progression of Parkinson's disease (PD). In the present work, we aim to predict motor outcome from baseline DAT SPECT imaging radiomic features and clinical measures using machine learning techniques. We designed and trained artificial neural networks (ANNs) to analyze the data from 69 patients within the Parkinson's Progressive Marker Initiative (PPMI) database. The task was to predict the unified PD rating scale (UPDRS) part III motor score in year 4 from 92 imaging features extracted on 12 different regions as well as 6 non-imaging measures at baseline (year 0). We first performed univariate screening (including theadjustment for false discovery) to select 4 regions each having 10 features with significant performance in classifying year 4 motor outcome into two classes of patients (divided by the UPDRS III threshold of 30). The leave-one-out strategy was then applied to train and test the ANNs for individual and combinations of features. The prediction statistics were calculated from 100 rounds of experiments, and theaccuracy in appropriate prediction (classification of year 4 outcome) was quantified. Out ofthe baseline non-imaging features, only the UPDRS III (at year 0) was predictive, while multiple imaging features depicted significance. The different selected features reached a predictive accuracy of 70% if used individually. Combining the top imaging features from the selected regions significantly improved the prediction accuracy to 75% (p < 0.01). The combination of imaging features with the year 0 UPDRS III score also improved the prediction accuracy to 75%. This study demonstrated the added predictive value of radiomic features extracted from DAT SPECT images in serving as a biomarker for PD progression tracking.