Search

Zur Differenzierung von neurodegenerativen und nicht-neurodegenerativen Ursachen eines klinisch unklaren Parkinsonsyndroms wird die Dopamintransporter-SPECT (DAT-SPECT) eingesetzt. Neben der visuellen Bildinterpretation unterst��tzt die semi-quantitative Analyse der striatalen Dopamintransporter-Verf��gbarkeit die Befundung. Die vorliegende Dissertationsschrift fasst drei Studien zusammen, die klinisch relevante Parameter der Bildentstehung und Bildverarbeitung in der semi-quantitativen Analyse der DAT-SPECT identifizierten, optimierten und hinsichtlich ihrer diagnostischen Genauigkeit untersuchten. In der ersten Studie wurde eine vollautomatische Methode zur Abgrenzung der ��u��eren Kopfkontur als Teil der Schw��chungskorrektur nach Chang implementiert und gegen��ber einer klinisch etablierten halbautomatischen Methode validiert. Die Auswertung eines multizentrischen Datensatzes ergab, dass beide Methoden zur Kopfabgrenzung sowohl vergleichbare semi-quantitative Werte als auch eine vergleichbare diagnostische Genauigkeit lieferten. Damit kann die vollautomatische Methode f��r den Einsatz in der klinischen Versorgung empfohlen werden, da keine Interaktion durch den Nutzer erforderlich ist. Die zweite Studie untersuchte zwei Methoden zur semi-quantitativen Absch��tzung der Tracer Bindung hinsichtlich ihrer diagnostischen Genauigkeit. Der aufl��sungsunabh��ngige specific uptake size index (SUSI) zeigte bei Datenerhebung an unterschiedlichen Kamerasystemen eine h��here diagnostische Genauigkeit als der Standardparameter, das sogenannte specific binding ratio (SBR). Dies ist besonders relevant f��r multizentrische Studien. Sobald jedoch nur ein Kamerasystem eingesetzt wurde, ist der Standardparameter SBR dem SUSI vorzuziehen, da dieser bei vergleichbarer diagnostischer Performance weniger anf��llig gegen��ber einer fehlerhaften Absch��tzung der nicht-spezifischen Tracer-Bindung in der Referenzregion ist. Ziel der dritten Studie war die Untersuchung des Einflusses der Gr����e der Normaldatenbank (NDB) auf die diagnostische Genauigkeit einer semi-quantitativen Auswertung der DAT-SPECT. Dabei erfolgte eine Simulation von unterschiedlichen Gr����en der NDB (n=5, 10, 15, ���, 50) durch zuf��lliges Ziehen aus dem Pool an Kontrollen und Validierung der jeweiligen NDB in der Gesamtkohorte anhand von Klassifizierungsgenauigkeit, Sensitivit��t und Spezifit��t. Die Analyse ergab, dass ein Mindestumfang von 25 bis 30 DAT-SPECT-Datens��tzen zur Bildung einer NDB notwendig ist. Eine Vergr����erung der NDB ��ber 40 F��lle hinaus f��hrt hingegen zu keiner weiteren relevanten Steigerung der diagnostischen Genauigkeit., Dopamine transporter SPECT (DAT-SPECT) is an established method to differentiate neurodegenerative and non-neurodegenerative causes in clinically uncertain parkinsonian syndromes. Besides visual image interpretation, semi-quantitative analysis of the striatal dopamine transporter availability is used to support medical diagnosis. The present doctoral thesis summarizes three studies that identified, optimized and validated clinically relevant, semi-quantitative parameters of DAT-SPECT image acquisition and processing with reference to their diagnostic accuracy. The first study proposed a fully automatic segmentation method of the outer head contour as a part of attenuation correction according to Chang and validated this method to a well-established semi-automatic method. Both methods for head delineation showed comparable semi-quantitative properties as well as comparable diagnostic accuracy based on multi-center patient data. For this reason, we suggest to use the fully automatic method in clinical patient care since no user interaction is required. A direct comparison of two semi-quantitative methods for estimation of tracer binding in reference to diagnostic accuracy was the aim of the second study. The spatial resolution independent specific uptake size index (SUSI) provided a higher diagnostic accuracy compared to the commonly used parameter, the specific binding ratio (SBR), when image acquisition is performed at various camera systems. This is highly relevant for multi-center image acquisition. However, in single-camera/mono-center settings SBR should be favored over SUSI, since SBR seemed to be less sensitive towards errors of the estimate of non-specific tracer uptake in the reference region with comparable diagnostic performance to SUSI. Rationale of the third study was to evaluate the impact of the size of the normal database (NDB) on the diagnostic performance of semi-quantitative analysis in DAT-SPECT. For it, simulation of NDB with different sizes (n=5, 10, 15, ���, 50) by randomly selecting subjects from the subcohort of normal controls was implemented and validation of each particular NDB based on the overall cohort was done concerning diagnostic accuracy, sensitivity and specificity as performance measures. The study results suggested that 25 to 30 DAT-SPECT data sets should be the minimum size of NDB. Increasing the size of NDB beyond 40 data sets provided only very small further improvement in diagnostic accuracy.

Additional file 1: Supplementary Table 1. A/T/N profiles across AD and prodromal AD subtypes. Supplementary Table 2. Structures defined in the Harvard-Oxford atlas that were used to measure the composite cortical volume. Supplementary Table 3. Hazard ratios for progression of subtypes of patients with prodromal AD to dementia. Supplementary Table 4. Mixed effects regression models of longitudinal cognitive decline across subtypes in the prodromal AD group; “no hypometabolism” subtype as reference. Supplementary Table 5. Mixed effects regression models of longitudinal cognitive decline across subtypes in the prodromal AD group; “limbic-predominant” subtype as reference. Supplementary Table 6. Comparisons between AD subtypes with respect to the ratio of inferior to medial temporal metabolism assessed with FDG-PET. Supplementary Table 7. Correlations between the HV: CTV ratio and cognitive measures in the AD and in the prodromal AD groups. Supplementary Table 8. Missing values (at baseline) for demographic, clinical and biomarker characteristics in the AD dementia and prodromal AD groups. Supplementary Figure 1. Determination of optimal clustering cutoff by objective criteria. Supplementary Figure 2. Hierarchical clustering dendrogram and hypometabolic FDG-PET patterns of resulting AD subtypes at higher cluster solutions. Supplementary Figure 3. Comparisons of hypometabolic FDG-PET patterns of subtypes of patients with AD. Supplementary Figure 4. Hypometabolic FDG-PET patterns of subtypes of patients with prodromal AD with adjusted scale.

Introduction The specific uptake size index (SUSI) of striatal FP-CIT uptake is independent of spatial resolution in the SPECT image, in contrast to the specific binding ratio (SBR). This suggests that the SUSI is particularly appropriate for multi-site/multi-camera settings in which camera-specific effects increase inter-subject variability of spatial resolution. However, the SUSI is sensitive to inter-subject variability of striatum size. Furthermore, it might be more sensitive to errors of the estimate of non-displaceable FP-CIT binding. This study compared SUSI and SBR in the multi-site/multi-camera (MULTI) setting of a prospective multi-center study and in a mono-site/mono-camera (MONO) setting representative of clinical routine. Methods The MULTI setting included patients with Parkinson’s disease (PD, n = 438) and healthy controls (n = 207) from the Parkinson Progression Marker Initiative. The MONO setting included 122 patients from routine clinical patient care in whom FP-CIT SPECT had been performed with the same double-head SPECT system according to the same acquisition and reconstruction protocol. Patients were categorized as “neurodegenerative” (n = 84) or “non-neurodegenerative” (n = 38) based on follow-up data. FP-CIT SPECTs were stereotactically normalized to MNI space. SUSI and SBR were computed for caudate, putamen, and whole striatum using unilateral ROIs predefined in MNI space. SUSI analysis was repeated in native patient space in the MONO setting. The area (AUC) under the ROC curve for identification of PD/“neurodegenerative” cases was used as performance measure. Results In both settings, the highest AUC was achieved by the putamen (minimum over both hemispheres), independent of the semi-quantitative method (SUSI or SBR). The putaminal SUSI provided slightly better performance with ROI analysis in MNI space compared to patient space (AUC = 0.969 vs. 0.961, p = 0.129). The SUSI (computed in MNI space) performed slightly better than the SBR in the MULTI setting (AUC = 0.993 vs. 0.991, p = 0.207) and slightly worse in the MONO setting (AUC = 0.969 vs. AUC = 0.976, p = 0.259). There was a trend toward larger AUC difference between SUSI and SBR in the MULTI setting compared to the MONO setting (p = 0.073). Variability of voxel intensity in the reference region was larger in misclassified cases compared to correctly classified cases for both SUSI and SBR (MULTI setting: p = 0.007 and p = 0.012, respectively). Conclusions The SUSI is particularly useful in MULTI settings. SPECT images should be stereotactically normalized prior to SUSI analysis. The putaminal SUSI provides better diagnostic performance than the SUSI of the whole striatum. Errors of the estimate of non-displaceable count density in the reference region can cause misclassification by both SUSI and SBR, particularly in borderline cases. These cases might be identified by visual checking FP-CIT uptake in the reference region for particularly high variability.

Increased blood glucose level (BGL) has been reported to cause alterations of FDG uptake in the brain that mimic Alzheimer’s disease (AD), even within the "acceptable" range ≤ 160 mg/dl. The aim of this study was (i) to confirm this in a large sample of well-characterized normal control (NC) subjects, and (ii) to analyze its impact on the prediction of AD dementia (ADD) in mild cognitive impairment (MCI). The study included NCs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that were cognitively stable for ≥36 months after PET (n = 87, 74.2 ± 5.3 y), and ADNI MCIs with ≥36 months follow-up if not progressed to ADD earlier (n = 323, 71.1 ± 7.1 y). Seventy-three of the MCIs had progressed to ADD within 36 months. In the NCs, parenchyma-scaled FDG uptake was tested for clusters of correlation with BGL on the family-wise, error-corrected 5% level. In the MCIs, ROC analysis was used to assess the power of FDG uptake in a predefined AD-typical region for prediction of ADD. ROC analysis was repeated after correcting mean FDG uptake in the AD-typical region for BGL based on linear regression in the NCs. In the NCs, BGL (59–149 mg/dl) was negatively correlated with FDG uptake in a cluster comprising the occipital cortex and precuneus but sparing the posterior cingulate, independent of amyloid-β and ApoE4 status. In the MCIs, FDG uptake in the AD-typical region provided an area of 0.804 under the ROC curve for prediction of ADD. Correcting FDG uptake in the AD-typical region for BGL (55–189 mg/dl) did not change predictive performance (area = 0.808, p = 0.311). Increasing BGL is associated with relative reduction of FDG uptake in the posterior cortex even in the "acceptable" range ≤ 160 mg/dl. The BGL-associated pattern is similar to the typical AD pattern, but not identical. BGL-associated variability of regional FDG uptake has no relevant impact on the power of FDG PET for prediction of MCI-to-ADD progression.

Positron emission tomography (PET) allows detecting molecular brain changes in vivo. However, the accuracy of PET is limited by partial volume effects (PVE) that affects quantitative analysis and visual interpretation of the images. Although PVE-correction methods have been shown to effectively increase the correspondence of the measured signal with the true regional tracer uptake, these procedures are still not commonly applied, neither in clinical nor in research settings. Here, we present an implementation of well validated PVE-correction procedures as a SPM toolbox, PETPVE12, for automated processing. We demonstrate its utility by a comprehensive analysis of the effects of PVE-correction on amyloid-sensitive AV45-PET data from 85 patients with Alzheimer's disease (AD) and 179 cognitively normal (CN) elderly. Effects of PVE-correction on global cortical standard uptake value ratios (SUVR) and the power of diagnostic group separation were assessed for the region-wise geometric transfer matrix method (PVEc-GTM), as well as for the 3-compartmental voxel-wise "Muller-Gartner" method (PVEc-MG). Both PVE-correction methods resulted in decreased global cortical SUVRs in the low to middle range of SUVR values, and in increased global cortical SUVRs at the high values. As a consequence, average SUVR of the CN group was reduced, whereas average SUVR of the AD group was increased by PVE-correction. These effects were also reflected in increased accuracies of group discrimination after PVEc-GTM (AUC=0.86) and PVEc-MG (AUC=0.89) compared to standard non-corrected SUVR (AUC=0.84). Voxel-wise analyses of PVEc-MG corrected data also demonstrated improved detection of regionally increased AV45 SUVR values in AD patients. These findings complement the growing evidence for a beneficial effect of PVE-correction in quantitative analysis of amyloid-sensitive PET data. The novel PETPVE12 toolbox significantly facilitates the application of PVE-correction, particularly within SPM-based processing pipelines. This is expected to foster the use of PVE-correction in brain PET for more widespread use. The toolbox is freely available at http://www.fil.ion.ucl.ac.uk/spm/ext/#PETPVE12.

This study is an attempt to draw a fundamental-educational comparison between the Progressive Education Movement (PEM) in the USA and People's education (PE) in the RSA. The connection between these two movements presumably lies in their progressive nature - therefore the purpose of this comparison is to expose the fundamental-educational resemblances between the PEM in the USA en PE in the RSA. This study is subsequently directed at the presentation of a fundamental-educational explanation for resemblances and differences found between concepts of progressiveness as propagated by the PEM in the USA and PE in the RSA. In order to gather and arrange data on the PEM in the USA and PE in the RSA, various methods such as literature study, the problem-historical method, comparative method, fundamental-reflective and descriptive method as well as the transcendental-critical method were employed. In chapter one the context, background, actuality and purpose of this research are presented, a methodological account is given, the research field is indicated and the structure of the research report is briefly outlined. Data in chapters two and three (wherein the PEM and PE, respectively, are typified and described) is essential, because the factors such as culturo-historical background, the spirit of the age and fundamental factors (such as fundamental religious motives and outlook on life) on which the relationship (presumably of a progressive nature) is based, are investigated by means of this information. Data gathered in chapters two and three is structured identically in order to clarify the purpose (the core) of the research, namely a fundamental-educational comparison between these two movements (chapter four). structuring of data in chapters two "and three (wherein the PEM and PE, respectively, are typified and described) highlights the culturo-historical background, concepts of progressiveness, philosophies and the educational-philosophical foundations of the PEM and PE as comparable thought systems. Literature study and the problem-historical method were primarily employed in arranging and adopting data for the purpose of this study. The fundamental-educational comparison in chapter four indicates the presence of more resemblances than differences in viewpoints on and handling of progressiveness by the PEM and PE. Resemblances found in viewpoints on progressiveness can presumably be explained by way of resemblances in religious apostasy freedom in nature I fundamental religious motive, the I humanistic-secular concept of life and biased emphasis on progression at the cost of tradition. The few differences in concepts of progressiveness held by the PEM and PE can presumably be explained by way of differences in their philosophical, pretheoretical and theoretical foundations. In chapter four primary use was made of the comparative method, fundamental-reflective and descriptive as well as the transcendental-critical method. In chapter five, the concluding chapter, a broad outline of the research is presented: findings, conclusions and recommendations are presented by virtue of the research. It was concluded inter alia that the PEM focuses on the inadequacies of the educational system in the USA up to the 1950's as well as on the social reconstruction that had to take place. PE on the other hand focuses on the shortcomings of the status quo and black education. It was concluded inter alia that, based on clear resemblances between their respective origins, the PEM can be regarded primarily as an embodiment of pragmatism and PE as an embodiment of Marxism. Recommendations are made inter alia that changes in education must be progressive- and simultaneously tradition-bound - then, and only then can progression be significant; bias and imbalance can be prevented and the entire process can acquire the true character of reformation in the Biblical sense. The PEM in the USA failed in this and PE in the RSA has, up to now, been unable to maintain the fine balance between tradition and progression. Thesis (MEd)--PU vir CHO, 1990