Cerebral F18 -FDG PET CT in Children: Patterns during Normal Childhood and Clinical Application of Statistical Parametric Mapping

The first aim was to recruit and analyse a high quality dataset of cerebral FDG PET CT scans in neurologically normal children. Using qualitative, semi-quantitative and statistical parametric mapping (SPM) techniques, the results showed that a pattern of FDG uptake similar to adults does not occur by one year of age as was previously believed, but the regional FDG uptake changes throughout childhood driven by differing age related regional rates of increasing FDG uptake. The second aim was to use this normal dataset in the clinical analysis of cerebral FDG PET CT scans in children with epilepsy and Neurofibromatosis type 1 (NF1). The normal dataset was validated for single-subject-versus-group SPM analysis and was highly specific for identifying the epileptogenic focus likely to result in a good post-operative outcome in children with epilepsy. Qualitative, semi-quantitative and group-versus-group SPM analyses were applied to FDG PET CT scans in children with NF1. The results showed reduced metabolism in the thalami and medial temporal lobes compared to neurologically normal children. This thesis has produced novel findings that advance the understanding of childhood brain development and has developed SPM techniques that can be applied to cerebral FDG PET CT scans in children with neurological disorders

A Standardized [18F]-FDG-PET Template for Spatial Normalization in Statistical Parametric Mapping of Dementia

n/

New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of 18F-DOPA and 11C-(+)-α-dihydrotetrabenazine (11C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, 18F-DOPA and 11C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of 11C-DTBZ PET. A symmetric reduction in striatal 11C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet

Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting.

PURPOSE The recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET. MATERIALS AND METHODS A total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aβ42 ( 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses. RESULTS Seven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis. CONCLUSION Our results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group

Automated Spatial Brain Normalization and Hindbrain White Matter Reference Tissue Give Improved [F-18]-Florbetaben PET Quantitation in Alzheimer's Model Mice

Preclinical PET studies of 13-amyloid (A beta) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for A beta-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of A beta burden (N = 40) were investigated by florbetaben PET Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter -reader agreement was assessed by Fleiss Kappa (kappa). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRc-rx/REF) relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all If kappa >= 0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRc-Fx, /REF " All SUVRG-Fx, /REF methods performed better than SUVGTx both with regard to longitudinal stability (d >= 1.21 vs. d = 0.23) and histological gold standard agreement (R >= 0.66 vs. R >= 0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (R-mean = 0.75

Voxel-based investigations of regional cerebral blood flow abnormalities in Alzheimer's disease using a single-detector SPECT system

PURPOSE: To evaluate the feasibility of using the Statistical Parametric Mapping (SPM) program for an automated, voxel-by-voxel assessment of regional cerebral blood flow (rCBF) deficits in Alzheimer's disease (AD) subjects relative to age-matched controls studied with a conventional, single-detector SPECT system. METHODS: We used a databank of 99mTc-HMPAO images of 19 patients with a diagnosis of probable AD and 15 elderly healthy volunteers; data were acquired using an Orbiter-Siemens single-detector SPECT system. Using SPM, images were transformed spatially, smoothed (12mm), and the data were compared on a voxel-by-voxel basis with t-tests. RESULTS: There were significant rCBF reductions in AD patients relative to controls involving regions predicted a priori to be affected in AD, namely the left temporal and parietal neocortices, and the right posterior cingulate gyrus (pOBJETIVO: Avaliar a viabilidade de emprego do programa Statistical Parametric Mapping (SPM) para investigar de forma automatizada, voxel-a-voxel, a presença de déficits de fluxo sanguíneo cerebral regional (FSCr) em pacientes com doença de Alzheimer (DA) comparados a sujeitos-controle pareados para idade, usando imagens de SPECT adquiridas com um equipamento convencional de detector único. MÉTODOS: Foi utilizado um banco de imagens adquiridas após injeção de 99mTc-HMPAO em 19 pacientes com diagnóstico provável de DA e 15 voluntários idosos saudáveis, usando um equipamento de SPECT Orbiter-Siemens de detector único. Empregando o programa SPM, as imagens foram transformadas espacialmente, suavizadas (12mm FWHM), e comparadas estatisticamente voxel-a-voxel entre os dois grupos, usando o teste de T. RESULTADOS: Foram identificadas reduções significativas de FSCr nos pacientes com DA comparados aos controles em regiões previstas a priori como afetadas por esta forma de demência, quais sejam os neocórtices temporal e parietal em hemisfério esquerdo e o cíngulo posterior direito (p<0,05, corrigido para comparações múltiplas). DISCUSSÃO: A localização dos focos de redução de FSCr em pacientes com DA no nosso estudo é, de forma geral, consistente com os achados de déficits cerebrais detectados em estudos anteriores de neuroimagem funcional na DA realizados com equipamentos de resolução espacial mais alta. Isto sugere o potencial de utilidade do programa SPM para a análise de dados de SPECT adquiridos com equipamentos de detector único, apesar da sensibilidade e resolução espacial limitadas de tais aparelhos

Voxel-based investigations of regional cerebral blood flow abnormalities in Alzheimer's disease using a single-detector SPECT system

PURPOSE: To evaluate the feasibility of using the Statistical Parametric Mapping (SPM) program for an automated, voxel-by-voxel assessment of regional cerebral blood flow (rCBF) deficits in Alzheimer's disease (AD) subjects relative to age-matched controls studied with a conventional, single-detector SPECT system. METHODS: We used a databank of 99mTc-HMPAO images of 19 patients with a diagnosis of probable AD and 15 elderly healthy volunteers; data were acquired using an Orbiter-Siemens single-detector SPECT system. Using SPM, images were transformed spatially, smoothed (12mm), and the data were compared on a voxel-by-voxel basis with t-tests. RESULTS: There were significant rCBF reductions in AD patients relative to controls involving regions predicted a priori to be affected in AD, namely the left temporal and parietal neocortices, and the right posterior cingulate gyrus (pOBJETIVO: Avaliar a viabilidade de emprego do programa Statistical Parametric Mapping (SPM) para investigar de forma automatizada, voxel-a-voxel, a presença de déficits de fluxo sanguíneo cerebral regional (FSCr) em pacientes com doença de Alzheimer (DA) comparados a sujeitos-controle pareados para idade, usando imagens de SPECT adquiridas com um equipamento convencional de detector único. MÉTODOS: Foi utilizado um banco de imagens adquiridas após injeção de 99mTc-HMPAO em 19 pacientes com diagnóstico provável de DA e 15 voluntários idosos saudáveis, usando um equipamento de SPECT Orbiter-Siemens de detector único. Empregando o programa SPM, as imagens foram transformadas espacialmente, suavizadas (12mm FWHM), e comparadas estatisticamente voxel-a-voxel entre os dois grupos, usando o teste de T. RESULTADOS: Foram identificadas reduções significativas de FSCr nos pacientes com DA comparados aos controles em regiões previstas a priori como afetadas por esta forma de demência, quais sejam os neocórtices temporal e parietal em hemisfério esquerdo e o cíngulo posterior direito (

Etablierung einer standardisierten Analyse longitudinaler Aβ-PET Scans zur effektiven Evaluation der BACE-Inhibition im transgenen Alzheimer-Mausmodell

Das erste Ziel der Promotionsarbeit war es eine optimale und standardisierte Analyse der Positron Emissions Tomographie in einem transgenen Kleintiermodell der Amyloid Anreicherung zu etablieren. Hierzu erfolgte die Evaluation einer automatisierten räumlichen Normalisierung und einer Intensitätsskalierung zu verschiedenen Referenzregionen. Insgesamt wurden 114 Aβ PET Scans des Mausmodells PS2APP mit dem Tracer FBB angefertigt. Darunter waren 37 Mäuse mit einem Baseline Scan (BL) im Alter von 8 Monaten und einem kurzfristigen Folgescan (FU) im Alter von 9,5 Monate, sowie 40 Scans im Alter von 13-16 Monaten (TER). Die so akquirierten microPET Dateien wurden durch eine starre, manuelle Fusion auf eine zerebrale MRT Vorlage durch drei Analysten mit unterschiedlichem Erfahrungsniveau untersucht. Im Anschluss wurden die Bilder durch Verwendung einer automatisierten, nicht-linearen Transformation auf altersabhängige Schablonen räumlich normalisiert und die Übereinstimmung der Analysten mittels Fleiss Kappa ermittelt. Zur Berechnung der zerebralen Amyloid Last definierten wir, neben dem reinen SUV (CTX), vier Referenzregionen mit den entsprechenden SUVR. Als Referenzregionen bestimmten wir den Hirnstamm (BST), das Zerebellum (CBL), die weiße Substanz (WM) und das gesamte Gehirn (GLM). Die Ergebnisse wurden anhand der longitudinalen Stabilität und der Übereinstimmung mit dem histologischen Goldstandart verglichen. Die räumliche Normalisierung resultierte in einer nahezu perfekten Übereinstimmung der Analysen. Die Korrelation zur Histologie blieb konstant oder verbesserte sich (alle κ ≥ 0.99). Alle SUVR waren der reinen SUV (CTX) überlegen (d ≥1.21 vs. d = 0.23 und R ≥ 0.66 vs. R ≥ 0.31). Eine Analyse der Skalierung zum GBM auf Voxelebene erbrachte einen physiologisch nicht erklärbaren Abfall der SUVR im Bereich des Rautenhirns. Die optimale Referenzregion definierten wir anhand der Korrelation mit der Histologie, der artifizielle Anhebung der Varianz in der Gruppe, der Effektgröße der longitudinalen kortikalen Amyloid Progression, den Effekt der Pathologie in der Referenzregion und den Einfluss einzelner Tiere. In Zusammenschau der untersuchten Qualitäten war die Intensitätsskalierung zur WM den übrigen SUVR überlegen. Auf Basis dieser Ergebnisse erfolgte im Anschluss, als zweiter Teil, eine multimodale Interventionsstudie zur Untersuchung der Amyloidose unter Therapie mit dem BACE-Inhibitor RO5508887. Hierzu wurden 26 weibliche PS2APP-Swe (TG) und 22 weibliche C57BL/6 (WT) Mäuse im Alter von 9,5 Monaten in einen Placeboarm (TG-VEH) und einen Interventionsarm (TG-BSI) randomisiert. Nach initialer Anfertigung eines Baseline [18F] -FBB PET Scans erfolgte die zweimal tägliche orale Applikation von RO5508887 oder einer entsprechenden Placebolösung über einen Zeitraum von 4 Monaten. Nach 10 und nach 18,5 Wochen wurde jeweils ein FU Scan angefertigt. Im Anschluss an den finalen Scan wurden die Gehirne der Tiere zur histologischen und biochemischen Quantifizierung und Differenzierung entnommen. Der Amyloid Progress war 15.3 ± 4.4% in der Placebo Gruppe und 8.4 ± 2.2% in der Therapiegruppe. Durch die Therapie konnte der Anstieg der Amyloidose signifikant reduziert werden (p<0.001). Diesen Effekt konnte die histologische Analyse in Bezug auf die Plaque-Belastung (-9,7%, p < 0,05) und die Plaque-Dichte (-9,9%, p <0,05) bestätigen. Auch die biochemische Analyse zeiget eine Reduktion des löslichen und unlöslichen Aβ40 ( -47% und -10%), sowie des löslichen und unlöslichen Aβ42 (-61% und -40%). Die akute BACE Inhibition konnte durch eine Reduktion des sAPP-β bei Anstieg des sAPP-α und unveränderten sAPP nachgewiesen werden. Außerdem stellte sich eine negative Korrelation zwischen dem Ausmaß der Amyloidose bei Therapiebeginn und dem Progress unter Therapie dar. Zusätzlich beobachteten wir eine weitere inverse Korrelation zwischen der naiven Amyloid Akkumulation und dem Therapieeffekt. So war die absolute Reduktion der Aβ Deposition unter Behandlung 7,6 ± 1,7% in hoch akkumulierenden Regionen (≥ 10%) und 4,8 ± 2,0% in niedrig akkumulierenden Regionen (<10%). Der relative Behandlungseffekt war 49 ± 11% in hochakkumulierenden Hirnregionen und 69 ± 28% in Regionen mit geringer naiver Akkumulation. In Regionen mit niedrigem, naivem Progresse konnte ein Schwellenwert der regionale Depositionsrate von 3,7%/18,5 Wochen bestimmt werden, unterhalb dem eine vollständige Blockierung der weiteren Signalzunahme angenommen werden kann. Zusammenfassend stellten wir die Überlegenheit einer Analyse von longitudinalen Aβ PET Daten im Mausmodell durch Verwendung einer räumlichen Normalisierung und einer SUVR mit Skalierung zur WM dar. Auf Basis dieser Erkenntnisse konnten wir im Anschluss zeigen, dass der Therapieeffekt einer BACE Inhibition auf den Progress der zerebralen Amyloidose von der Aβ-Last bei Therapiebeginn abhängig ist