Stroke is one of the leading causes of death and disability worldwide with 20% of ischemic strokes attributed to carotid atherosclerosis. In recent years, morphological characteristics of atherosclerotic plaque such as a thin fibrous cap, large lipid-rich necrotic core, intraplaque haemorrhage and ulceration have shown correlations with subsequent clinical events. High resolution, multi-contrast magnetic resonance imaging (MRI) can qualitatively identify these features and monitor disease progression. Compared to traditional contrast weighted imaging, quantitative MRI could provide an objective assessment of disease. Therefore, the general hypothesis investigated in this thesis is: Quantitative MRI methods can be used to acquire objective biomarkers of carotid vessel wall and atherosclerotic plaque, with high accuracy and good repeatability. The research presented in this thesis describes the use of multiple quantitative MRI methods to evaluate the carotid vessel wall. These include dynamic contrast-enhanced (DCE) MRI analysis for the assessment of plaque inflammation/neovascularization and the development of black-blood quantitative T2/T2* mapping sequences for plaque component characterisation. The acceleration of the sequences was also investigated using a combination of compressed sensing (CS) and parallel imaging (PI). Chapter 3 investigated the hypothesis that plaque functional characteristics and surface morphology can be evaluated using a high temporal and spatial resolution 4D contrast-enhanced MRI/MR angiography (MRA) sequence. Chapter 4 tested the hypothesis that magnetisation prepared 3D fast-spin-echo (FSE) is the best sequence for in vivo T2 mapping. Four different black-blood T2 mapping sequences were developed and compared in phantom and volunteers. Chapter 5 tested the hypothesis that the optimised iMSDE 3D FSE T2 mapping sequence can be combined with CS and PI to further reduce the acquisition time without significantly affecting image quality and the measured T2 relaxation times. Chapter 6 investigated the hypothesis that compressed sensing can be used to reduce the overall examination time of a comprehensive multi-contrast MRI protocol, comprising black-blood T1 weighted, T2 weighted and proton density weighted sequences. Finally, Chapter 7 investigated the hypothesis that accurate 3D vessel wall R2* mapping can be achieved through black-blood preparation. In summary, this thesis investigated the use of multiple quantitative MRI methods in evaluating the carotid vessel wall and atherosclerotic plaque. The results demonstrate that quantitative MRI is an accurate and reproducible method for the carotid plaque characterization.

Introduction: The Elastography Software Library (ESL) was developed to achieve clinically feasible, super-resolution (SR) Magnetic Resonance Elastography (MRE). ESL was created by accomplishing four objectives: 1. perform a critical analysis of MRE inversion, using discrete-time Fourier transform (DTFT) methods, to enable selection of the wave inversion approach most suitable to high- and SR MRE (Chapter 2) 2. develop a new method for real-time 4D phase unwrapping, to enable large acquisitions to be processed in clinical work ow (Chapter 3) 3. develop a new inversion pipeline that recovers fine features in elastograms (Chapter 4) 4. extend this pipeline with a novel interpolation technique to achieve super-resolution (Chapter 5) The results of these experiments were combined to make the ESL. Over the course of the work, two objectives also resulted in software applications in their own right (PhaseTools for phase unwrapping, and Elastography Software Pipeline (ESP) for fine feature elasticity map recovery). Methods: Critical Analysis: Two-filter cascades were designed to model the signal processing pipelines found in the present MRE literature. These models were subjected to DTFT-based analysis to determine the relative advantage of various mathematical approaches to the MRE inverse problem. Phase Unwrapping: A test data set was developed to measure algorithm performance in 4D on data sets with varying levels of wrap, gradient and noise. The algorithms that performed most accurately and efficiently on test data were then applied to in vivo brain, liver, and muscle data, of both moderate and severe wrap, and inspected for wrap failure. Fine Feature Recovery: A new MRE image processing pipeline was developed that incorporates wavelet-domain denoising, image-driven noise estimation, and feature detection. ESP was first validated using simulated data, including viscoelastic Finite Element Method (FEM) simulations, at multiple noise levels. ESP images were then compared with Multifrequency Dual Elasto-Visco Inversion (MDEV) pipeline images in three ten-subject cohorts of brain, thigh, and liver acquisitions. Finally the proportion of spectral energy at fine frequencies was quantified using the Reduced Energy Ratio (RER) for both ESP and MDEV. Super-Resolution: An extension of the ESP pipeline was developed that incorporated a new image fusion technique to combine non-redundant information. The algorithm was validated on an analytic simulation program developed for the study. An in vivo cross-validation was performed between 1X, 2X and 4X magnification levels measuring both spectral gains and shear modulus values. Results: Critical Analysis: The more complex, heterogeneous FEM models were found to only outperform Algebraic Helmholtz Inversion (AHI) in very low noise, with Gaussian smoothing of σ > 0:8px or Butterworth low-pass cutoffs of < 0:8π negating any advantages from assumption of local heterogeneity. Phase Unwrapping: Three algorithms were determined to perform with sufficient robustness in real-time on 4D data sets with challenging phase wrap. These algorithms were then applied to in vivo brain, skeletal muscle, liver and phantom data and shown to successfully resolve heavy phase wrap within a \real-time" criterion of under 3 minutes. Fine Feature Recovery: For FEM inversions, mean values of background and soft target simulated results remained within 8% of prescribed up to σ = 10% for both jG*j and ϕ, though inspection of the ϕ image showed scatter- and boundary-related artefacts around the soft target. Hard target results showed jG*j means within 7% of prescribed up to σ = 5% but unreliable ϕ means, and inspection showed showed scatter- and boundary-related artefacts. For the in vivo cohorts, ESP results showed mean correlation of R = 0:83 with MDEV and liver stiffness estimates within 7% of Local Frequency Estimation (LFE) results. Finally, ESP showed statistically significant increase in fine feature spectral energy as measured with RER for both jG*j (p < 1X10-9) and ϕ (p < 1X10-3). Super-Resolution: At 4X SR, both brain and liver cohorts showed a highly significant (p ≤ 10-6) increase in both number of recovered frequencies and normalised spectral energy in those recovered frequencies. Both the 2X and 4X SR techniques showed a decrease in stiffness estimate from the original resolution (mean decrease of 11.6% and 14.0%) respectively; however cohort correlations between SR and original values were upwards of R = 0:988. Discussion: Established as a technique highly sensitive to important tissue changes, MR Elastography is now also a finely-featured super resolution technique in two parameters, enabling new clinical and research applications. Future work includes statistical mapping of both localised and diffuse soft tissue changes, rapid computation on heterogeneous processing architectures, and two-parameter super-resolution MRI-based lesion mapping.

Tracer based MRI perfusion measurements is a clinically useful tool to assess regional distributions of tissue blood flow and volume. The method may be based on any of the three relaxation mechanisms T1, T1 and T2*, the latter denoted DSC-MRI being the most common. The primary aim of this work was to study the feasibility of obtaining quantitative estimates using these methods. 1) Feasibility of DSC-MRI for kidneys using an iron oxide based contrast agent and the influence of secondary relaxation effects on the results, part of a clinical phase II trial: The method proved feasible and the underestimation induced by secondary relaxation can be corrected for by using a double echo sequence. 2) Influence of blood flow rate on risk factors for developing cerebral ischemia during cardio pulmonary bypass, measurements in pig with gadolinium based DSC-MRI: The results indicated an ischemic threshold level at a blood flow rate of approximately 6 ml/kg/min. 3) The ability of gadolinium based DSC-MRI to detect changes in global blood flow, experimental measurements in pig and numerical simulations: The results support that DSC-MRI can discriminate between global flow levels in the same subject given that all other parameters are kept constant. The results also indicate that calculated perfusion values are highly sensitive to the arterial deconvolution procedure. 4) Influence of differences in blood/tissue relaxivity and secondary relaxation for a gadolinium based contrast agent, measurements in pig and numerical simulations: The blood/tissue relaxivity ratio is not unity and the situation is complicated by secondary relaxation effects. Deconvolution regularization appears to partly counteract the overestimation induced by difference in blood/tissue relaxivity for DSC-MRI. In summary, the fundamental assumption of equal blood and tissue relaxivity is experimentally shown to be invalid and the influence of this discrepancy is substantial. Several factors contribute to measurement errors, a combination of these factors can incidentally lead to additive errors or error cancellation based on a variety of experimental and analysis conditions. Given that the differences in blood/tissue relaxivity cannot readily be accounted for in a clinical setting, absolute perfusion quantification by tracer based MRI remains challenging if not impossible.

The increasing demands for improving magnetic resonance imaging (MRI) quality, especially reducing the imaging time have been driving the channel number of parallel magnetic resonance imaging (Parallel MRI) to increase. When the channel number increases to 64 or even 128, the traditional method of stacking the same number of radio-frequency (RF) receivers with very low level of integration becomes expensive and cumbersome. However, the cost, size, power consumption of the Parallel MRI receivers can be dramatically reduced by designing a whole receiver front-end even multiple receiver front-ends on a single chip using CMOS technology, and multiplexing the output signal of each receiver front-end into one channel so that as much hardware resource can be shared by as many channels as possible, especially the digitizer. The main object of this research is focused on the analysis and design of fully integrated multi-channel RF receiver and multiplexing technology. First, different architectures of RF receiver and different multiplexing method are analyzed. After comparing the advantages and the disadvantages of these architectures, an architecture of receiver front-end which is most suitable for fully on-chip multi-channel design is proposed and a multiplexing method is selected. According to this proposed architecture, a four-channel receiver front-end was designed and fabricated using TSMC 0.18μm technology on a single chip and methods of testing in the MRI system using parallel planar coil array and phase coil array respectively as target coils were presented. Each channel of the receiver front-end includes an ultra low noise amplifier (LNA), a quadrature image rejection down-converter, a buffer, and a low-pass filter (LPF) which also acts as a variable gain amplifier (VGA). The quadrature image rejection downconverter consists of a quadrature generator, a passive mixer with a transimpedance amplifier which converts the output current signal of the passive mixer into voltage signal while acts as a LPF, and a polyphase filter after the TIA. The receiver has an over NF of 0.935dB, variable gain from about 80dB to 90dB, power consumption of 30.8mW, and chip area of 6mm2. Next, a prototype of 4-channel RF receiver with Time Domain Multiplexing (TDM) on a single printed circuit board (PCB) was designed and bench-tested. Then Parallel MRI experiment was carried out and images were acquired using this prototype. The testing results verify the proposed concepts.

Parallel magnetic resonance (MR) imaging may be used to increase either the throughput or the speed of the MR imaging experiment. As such, parallel imaging may be accomplished either through a "parallelization" of the MR experiment, or by the use of arrays of sensors. In parallelization, multiple MR scanners (or multiple sensors) are used to collect images from different samples simultaneously. This allows for an increase in the throughput, not the inherent speed, of the MR experiment. Parallel imaging with arrays of sensor coils, on the other hand, makes use of the spatial localization properties of the sensors in an imaging array to allow a reduction in the number of phase encodes required in acquiring an image. This reduced phase-encoding requirement permits an increase in the overall imaging speed by a factor up to the number of sensors in the imaging array. The focus of this dissertation has been the development of cost-effective instrumentation that would enable advances in the state of the art of parallel MR imaging. First, a low-cost desktop MR scanner was developed (< $13,000) for imaging small samples (2.54 cm fields-of view) at low magnetic field strengths (< 0.25 T). The performance of the prototype was verified through bench-top measurements and phantom imaging. The prototype transceiver has demonstrated an SNR (signal-to-noise ratio) comparable to that of a commercial MR system. This scanner could make parallelization of the MR experiment a practical reality, at least in the areas of small animal research and education. A 64-channel receiver for parallel MR imaging with arrays of sensors was also developed. The receiver prototype was characterized through both bench-top tests and phantom imaging. The parallel receiver is capable of simultaneous reception of up to sixty-four, 1 MHz bandwidth MR signals, at imaging frequencies from 63 to 200 MHz, with an SNR performance (on each channel) comparable to that of a single-channel commercial MR receiver. The prototype should enable investigation into the speed increases obtainable from imaging with large arrays of sensors and has already been used to develop a new parallel imaging technique known as single echo acquisition (SEA) imaging.

MRI is a versatile tool for systematically assessing anatomical and functional changes in small animal models of human disease. Its noninvasive nature makes MRI an ideal candidate for longitudinal evaluation of disease progression in mice; however achieving the desired level of statistical power can be expensive in terms of imaging time. This is particularly true for cancer studies, where dynamic contrast-enhanced (DCE-) MRI, which involves the repeated acquisition of anatomical images before, during, and after the injection of a paramagnetic contrast agent, is used to monitor changes in tumor vasculature. A means of reducing the overall time required to scan multiple cohorts of animals in distinct experimental groups is therefore highly desirable. Multiple-mouse MRI, in which several animals are simultaneously scanned in a common MRI system, has been successfully used to improve study throughput. However, to best utilize the next generation of small-animal MRI systems that will be equipped with an increased number of receive channels, a paradigm shift from simultaneously scanning as many animals as possible to scanning a more manageable number, at a faster rate, must be considered. Given a small-animal MRI system with 16 available receive channels, the simulations described in this work explore the tradeoffs between the number of animals scanned at once and the number of array elements dedicated to each animal for maximizing throughput. An array system consisting of 15 receive and 5 transmit coils allows throughput-optimized acceleration of a DCE-MRI protocol by a combination of multi-animal and parallel imaging techniques. The array system was designed and fabricated for use on a 7.0-T / 30-cm MRI system, and tested for high-throughput imaging performance in phantoms. Results indicate that up to a nine-fold throughput improvement is possible without sacrificing image quality compared to standard single-animal imaging hardware. A DCE-MRI study throughput improvement of just over six times that achieved with conventional single-mouse imaging was realized. This system will lower the barriers for DCE-MRI in preclinical research and enable more thorough sampling of disease pathologies that progress rapidly over time. / text

The Cartesian Cubic lattice is known to be sub optimal when consideringband-limited signals but is still used as standard in three-dimensional medical magneticresonance imaging. The optimal sampling lattices are the body-centered cubic latticeand the face-centered cubic lattice. This report discusses the possible use of thesesampling lattices in MRI and presents verification of the non standard Fouriertransform method that is required for MR image creation for these sampling lattices.The results show that the Fourier transform is consistent with analytical models.

Obesity is a pervasive condition associated with increased risk of dementia, cognitive impairment, and cerebral atrophy in later life. Given that the pathophysiology underlying obesity’s impact on the central nervous system is poorly understood, the current study examined the association between body mass index (BMI) and five cerebral metabolites of neurobiological significance: N-acetyl-aspartate (NAA), a marker of neuronal viability; choline-containing compounds, free choline, phosphocholine and glycerophosphocholine (Cho), markers of membrane breakdown and turn over; creatine (Cr), a marker of energy metabolism; myo-inositol (mI), an organic osmolyte and substrate for the synthesis of the secondary messenger, inositol triphosphate; and glutamate (Glu), a marker of excitatory neurotransmission and synaptic integrity. Fifty-five participants, aged 40-60 years, underwent neuropsychological testing, health screen and proton magnetic resonance spectroscopy (1H MRS) of the occipitoparietal grey matter. Concentrations of NAA, Cho, mI, and Glu were calculated as a ratio over Cr and examined in relation to BMI using multivariate multiple regression. Higher BMI was associated with elevations in mI/Cr (F(5,47)=3.583, p=0.008, ß=0.387, p=0.006), independent of age, sex, fasting glucose levels, and systolic blood pressure. The current study found that higher BMI is related to increased concentrations of the organic osmoltye and glial marker myo-inositol, potentially implicating plasma hypertonicity and neuroinflammation as mechanisms underlying obesity-related brain dysfunction. With validation and absolute quantification, studies of neurometabolites may improve identification of the pathological mechanisms underlying obesity’s consequences on cognition. / text

El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno del neurodesarrollo caracterizado por síntomas de inatención, hiperactividad e impulsividad. Los modelos clásicos acerca de la neuroanatomía del trastorno apuntan a alteraciones en los circuitos fronto-estriado-cerebelares. Los estudios de neuroimagen estructural apoyan parcialmente estos modelos. Sin embargo, casi todos estos estudios se basan en el análisis de regiones seleccionadas a priori (procedimiento que se conoce como ROI, acrónimo inglés de regiones de interés: "region of interest"). Estudios más recientes basados en aproximaciones globales apuntan a que las alteraciones estructurales no se limitan a los circuitos fronto-estriado-cerebelares, sino que también afectan las regiones temporales, parietales y cinguladas.El objetivo de la presente tesis es el de redefinir y aplicar dos métodos de análisis estructural complementarios para identificar los circuitos cerebrales alterados en el TDAH así como para relacionar dichos circuitos con los diferentes subtipos clínicos. Para tal fin, presentaremos y discutiremos dos estudios de resonancia magnética estructural (Carmona et al. 2005; Tremols et al. 2008). Estos dos estudios representan una novedad y mejora de estudios de TDAH previos, por dos razones principales: a) la aplicación por primera vez un estudios basado en la morfometría de vóxeles para comparar el cerebro de niños con TDAH con el cerebro de niños controles no relacionados familiarmente; b) el diseño e implementación de un nuevo método, fácil de aplicar, de segmentación manual del núcleo caudado.Los resultados confirman los datos obtenidos en estudios previos acerca de menor volumen cerebral en niños con TDAH, y localizan esta reducción en determinadas regiones de sustancia gris. A parte de confirmar las alteraciones fronto-estriado-cerebelares hayamos reducciones en áreas parietales, cingulares y temporales. En concreto observamos decrementos volumétricos de sustancia gris en la corteza frontal inferior, el estriado dorsal, la corteza parietal inferior y la corteza cingulada posterior, regiones clásicamente relacionadas con problemas de inhibición, deficits de memoria de trabajo y alteraciones en tareas de atención visuoespacial, respectivamente. También observamos reducciones volumétricas en áreas típicamente emocionales, como la corteza orbitofrontal, el estriado ventral y las estructurales temporales mediales deficits que podrían explicar las disfunciones motivacionales así como las alteraciones en el procesamiento del refuerzo. Curiosamente, las reducciones de sustancia gris en áreas relacionadas con el procesamiento emocional son más pronunciadas en el subtipo hiperactivo-impulsivo, algo menos en el subtipo combinado y casi inexistentes en el subtipo inatento. Esta diferente afectación en función de los subtipos va en la línea de teorías neuroanatómicas actuales acerca del TDAH (Castellanos and Tannock 2002). También observamos déficits de sustancia gris en áreas sensorio-motoras (específicamente en la corteza perirrolándica y el área motora suplementaria), y en el cerebelo. Por un lado, los déficits en áreas sensorio-motoras probablemente reflejan los problemas de psicomotricidad fina que presentan muchos de los niños con TDAH. Sin embargo, el hecho de que estas reducciones sean especialmente prominentes en los subtipos combinado e inatento, sugieren la posibilidad de que estas alteraciones estén especialmente relacionadas con los déficits atencionales. En base a esto, hipotetizamos que las alteraciones en estas regiones producirían un déficit para integrar y actualizar la información procedente del mundo exterior y, a su vez darían lugar a un sesgo a favor del procesamiento de los estados internos resultando en inatención. Por otro lado, las reducciones cerebelares (extensamente observadas en la literatura del TDAH) parecen están relacionadas con los déficits cognitivos, los afectivos y los emocionales. Creemos que la implicación del cerebelo en estas disfunciones estaría vehiculada por el papel de esta estructural como moduladora del flujo de información entre los circuitos fronto-estriatales. Finalmente nuestros hallazgos son los primeros en demostrar alteraciones diferenciales en la cabeza y el cuerpo del núcleo caudado en el TDAH. Esta desigual implicación de las diferentes partes del núcleo caudado explicaría en parte la heterogeneidad de los estudios previos. Como conclusión, las reducciones volumétricas de sustancia gris en áreas cognitivas y emocionales apoyan la implicación de disfunciones en los circuitos fronto-estriatales llamados cool (cognitivos) y hot (emocionales) respectivamente. Hasta la fecha este es el primer estudio neuroanatómico que apoya la existencia de disfunciones tanto cognitvas como emocionales en niños con TDAH. Nuestros hallazgos constituyen la primera evidencia neuroanatómica a favor de los modelos de doble ruta porpuestos por Sonuga-Barke (Sonuga- Barke 2002; Sonuga-Barke 2003).REFERENCIAS: 1. Tremols V, Bielsa A, Soliva JC, Raheb C, Carmona S, Tomas J, et al. (2008): Differential abnormalities of the head and body of the caudate nucleus in attention deficit-hyperactivity disorder. Psychiatry Res. 163:270-278.2. Carmona S, Vilarroya O, Bielsa A, Tremols V, Soliva JC, Rovira M, et al. (2005): Global and regional gray matter reductions in ADHD: a voxel-based morphometric study. Neurosci Lett. 389:88-93.3. Castellanos FX, Tannock R (2002): Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 3:617-628.4. Sonuga-Barke EJ (2003): The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev. 27:593-604.5. Sonuga-Barke EJ (2002): Psychological heterogeneity in AD/HD--a dual pathway model of behaviour and cognition. Behav Brain Res. 130:29-36. / Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease characterized by symptoms of inattention, hyperactivity and impulsivity. Data from different studies point to ADHD abnormalities in fronto-striatal circuits. Structural neuroimaging studies partially support fronto-striatal abnormalities and suggest an important role of the cerebellum. However, nearly all these studies are based on the analysis of apriori selected regions of interest (known as ROI approaches). Recent studies, using more global approaches, found that ADHD structural abnormalities were not limited to fronto-striatal-cerebellar circuits, but also affect temporal, parietal and cingulate regions.The aim of the present dissertation is to refine and apply two complementary methods of structural neuroimaging, in order to identify the brain circuits altered inADHD and relate them to different clinical ADHD subtypes and to known ADHD neuropsychological deficits. For that purpose, two structural MRI studies will be presented and discussed (Carmona et al. 2005; Tremols et al. 2008). The differential contributions of these studies, which represent a novelty and an improvement of previous ADHD studies, are: a) the application for the first time ofvoxel-based morphometry analysis to compare ADHD children with non family related control children; b) the design and application of a new, easy to apply, manual method of caudate nucleus segmentation.The results confirm previous findings about smaller brain volume in ADHD children, and refine this reduction by attributing it to grey matter (GM) volume. We also confirm abnormalities in fronto-striatal-cerebellar circuits as well as in parietal, cingulate and temporal regions. Specifically, we observed reductions in inferior frontal cortex, dorsal striatum, inferior parietal cortex and posterior cingulate cortex; thus explaining inhibition problems, spatial working memory deficits and visuospatial attentional alterations. We also observed GM volume reductions in emotionally driven areas such as orbitofrontal cortex, ventral striatum and middle temporal structures; thus accounting for dysfunctional delayed reward and motivational deficits. Interestingly, GM volume reductions, related to emotional processes are more prominent in H-I subtype, more preserved in combined subtypes, and relatively undisrupted in inattentive subtypes, which is in agreement with previous ADHD theories (Castellanos and Tannock 2002). We have also found GM deficits in "sensori-motor" areas (specifically in perirolandic cortex and supplementary motor area), and in the cerebellum. On the one hand, deficits in sensori-motor areas probably reflect problems in fine motor coordination. However, the fact that these reductions are especially prominent in combined and inattentive subtypes brings up the possibility that they may be related to attentional dysfunctions.I hypothesized that deficits in these regions may produce a deficit when integrating and updating information from the external world and, in turn, produce a bias toward internal world focusing, thus, resulting in inattention. On the other hand, cerebellar reductions (which are extensively reported in ADHD literature) seem to be related to all cognitive, affective and sensorimotor deficits. The implication of cerebellum in all these dysfunctions may arise from its role as a modulator of the flow of information between fronto-strital circuits. Finally, our findings are also the first to show caudate head and body differential abnormalities in ADHD, which explain previous heterogeneous results, providing a new and reliable method to study striatal structures.As a conclusion, GM volume reductions in emotional and cognitive areas support the implication of both hot (emotional) and cool (cognitive) functions, which agrees with most neuropsychological accounts of ADHD. To our knowledge this is the first time that a neuroanatomical study provides support for the existence of both cognitive and emotional dysfunctions in ADHD children. If these findings are replicated, they will constitute critical evidence for Sonuga-Barke's theory (Sonuga- Barke 2002; Sonuga-Barke 2003) about the dual route model.REFERENCIAS: 1. Tremols V, Bielsa A, Soliva JC, Raheb C, Carmona S, Tomas J, et al. (2008): Differential abnormalities of the head and body of the caudate nucleus in attention deficit-hyperactivity disorder. Psychiatry Res. 163:270-278.2. Carmona S, Vilarroya O, Bielsa A, Tremols V, Soliva JC, Rovira M, et al. (2005): Global and regional gray matter reductions in ADHD: a voxel-based morphometric study. Neurosci Lett. 389:88-93.3. Castellanos FX, Tannock R (2002): Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 3:617-628.5. Sonuga-Barke EJ (2003): The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev. 27:593-604.6. Sonuga-Barke EJ (2002): Psychological heterogeneity in AD/HD--a dual pathway model of behaviour and cognition. Behav Brain Res. 130:29-36.

Dissertation zur Erlangung des akademischen Grades Dr. med. Grenzwertversatilität, Intra- und Interobservervariabilität bei der Befundung verschiedener kardialer MRT-Sequenzen bei Myokarditis eingereicht von Julia Kriemhild Steiner Problemstellung Die akute virale Myokarditis, als sekundäre Entzündung des Herzmuskelgewebes durch kardiotrope Viren, kann vollständig ausheilen oder über eine chronische Myokarditis zu einer dilatativen Kardiomyopathie führen. Dabei können maligne Herzrhythmusstörungen auftreten und es kann zum plötzlichen Herztod kommen. Eine definitive Diagnose ist somit von entscheidender Bedeutung, um interventionsbedürftige Formen zu behandeln und Differentialdiagnosen auszuschließen. Als Goldstandard der Myokarditis-Diagnostik gilt die Endomyokardbiopsie (EMB). Diese birgt als invasive Methode jedoch auch Risiken für den Patienten. Die kardiale Magnet-Resonanz-Tomographie (MRT) stellt eine strahlenfreie, nicht-invasive und damit risikoarme Alternative dar. Ziel dieser Arbeit war es, die Intra- und Interobservervariabilität kardialer MRT-Parameter bei der Diagnostik einer Myokarditis zu evaluieren. Außerdem wurde die Grenzwertversatilität der MRT-Parameter „edema-ratio“ (ER) und „early gadolinium enhancement“ (gRE) bei Myokarditis auf einem Philips-Scanner untersucht. Material und Methode Diese prospektive Studie am Herzzentrum Leipzig hat von 2007 bis 2009 kardiale MRT-Sequenzen von Patienten ausgewertet, bei denen klinisch der Verdacht auf eine akute virale Myokarditis bestand. Alle Patienten erhielten zur Verifizierung der Diagnose eine Linksherz-EMB. Die Arbeit besteht aus zwei Patientenkollektiven. Bei 52 Patienten (36 männliche Patienten, 16 weibliche Patientinnen; Mittelwert Alter: 49,42 Jahre ± 15,78 (Standardabweichung), Altersbereich zwischen 19-77 Jahre) wurde die Intra- und Interobservervariabilität bei der Auswertung der MRT-Parameter ER (edema-ratio) und gRE (early gadolinium enhancement) evaluiert. Dabei wurde in der STIR die ER berechnet und in der T1 FSE das gRE. Dieses erfolgte durch zwei verblindete Untersucher. Untersucher A war dabei „erfahren“ (> 100 Untersuchungen), Untersucher B (< 50 Untersuchungen) „unerfahren“. Die Analyse erfolgte statistisch durch lineare Regressionsanalysen und Bland-Altman-Plots. Das zweite Kollektiv umfasste 100 Patienten (79 männliche Patienten, 21 weibliche Patientinnen; Mittelwert Alter 46,39 Jahre ± 16,78 (Standardabweichung), Altersbereich zwischen 18-79 Jahre) mit klinischem Verdacht auf akute virale Myokarditis. Es wurde die Grenzwertversatilität der MRT-Parameter ER und gRE bei der Diagnostik einer Myokarditis auf einem Philips-Scanner untersucht. Die Auswertung der MRT-Sequenzen erfolgte durch einen erfahrenen Untersucher (>100 Untersuchungen). Dabei wurde in der STIR die Edema-Ratio (ER) berechnet und in der T1 FSE das „early gadolinium enhancement“ (gRE). Die Analyse erfolgte statistisch durch Receiver-Operating-Characteristic- Kurven (ROC-Kurven). Ergebnisse Die Evaluation der Intra- und Interobservervariabilität ergab für den „erfahrenen“ Untersucher A eine gute Korrelation bei der Auswertung des MRT-Parameters ER (r=0.96, CI95 r= 0.93-0.98, p < 0.0001) und der Auswertung des MRT-Parameters gRE (r=0.93, CI95 r= 0.89-0.96, p < 0.0001). Für den „unerfahrenen“ Untersucher B stellte sich ein höhere Intraobservervariabilität sowohl bei der Untersuchung der ER (r=0.85, CI95 r=0.75-0.91, p < 0.0001), als auch bei der Untersuchung des gRE (r=0.57, CI95 r=0.36-0.73, p < 0.0001) heraus. Damit war die Interobservervariabilität höher bei der Auswertung des gRE (r=0.60, CI95 r=0.36-0.73, p < 0.0001), als bei der Auswertung der ER (r=0.86, CI95 r=0.76-0.91, p < 0.0001). Die Auswertung des zweiten Patientenkollektivs erfolgte mit Receiver-Operating-Characteristic-Kurven (ROC-Kurven). Als Goldstandard diente, bei Ausnahme einer Sub-Gruppe, die EMB. Für das Gesamtkollektivs dieser Arbeit ergab die Fläche unter der Kurve (AUC) für die ER 0,59 (CI95; 0.474, 0.706) und für das gRE 0.59 (CI95: 0.444,0.672). AUC-Werte nahe der 0.5 deuten auf einen Zufallsprozess hin. Die resultierenden Häufigkeitsverteilungen ergaben bei einem Grenzwert (cut-off) von 1,95 für die ER eine Sensitivität von 64% und eine Spezifität von 59%, für das gRE bei einem Grenzwert von 4,05 eine Sensitivität von 72% und eine Spezifität von 29%. Auf Grund der unbefriedigenden Ergebnisse der ROC-Analysen wurden Subgruppen gebildet, um die Grenzwertversatilität der MRT-Parameter ER und gRE auf einem Philips-Scanner zu evaluieren, da von der Annahme ausgegangen wurde, dass verschiedene Grenzwerte für die Parameter ER und gRE an unterschiedlichen MRT-Scannern bestehen. Die Analyse des Kollektiv akute Myokarditis (Definition: Symptombeginn < 14 Tagen) ergab für die ER bei einem cut-off von 1,95 eine Sensitivität von 67% und eine Spezifität von 56%. Bei dem gRE zeigte sich bei einem cut-off von 4,05 eine Sensitivität von 81% und eine Spezifität von 56%. Bei einem cut-off von 4,55 eine Sensitivität von 69% und eine Spezifität 69%. Ähnliche Ergebnisse zeigt die Analyse der Subgruppe chronische Myokarditis (Definition: Symptombeginn > 14 Tagen), die für die ER bei einem cut-off von 1,95 eine Sensitivität von 78% und Spezifität von 40% zeigte und für das gRE bei einem cut-off von 4,55 eine valide Sensitivität von 78% und Spezifität von 80%. Es wurde noch eine Analyse der Sub-Gruppe klinisch akute Myokarditis (Definition: Symptombeginn < 7 Tagen, Troponin T oder I positiv, St-Hebungen im Elektrokardiogramm) durchgeführt, wobei hier der Goldstandard geändert wurde. Statt der EMB wurde hier die „Klinik“ als Goldstandard genutzt. Hier zeigte sich erneut für die ER bei einem cut-off von 1,95 bei einer Sensitivität von 78% und Spezifität von 40% und für das gRE bei einem cut-off von 4,55 bei einer Sensitivität von 78% und Spezifität von 80% die validesten Ergebnisse. Schlussfolgerung In dieser Arbeit konnte gezeigt werden, dass die Intra- und Interobserver Variabilität sehr von der Erfahrung des jeweiligen Untersuchers abhängig ist. Das bedeutet, dass die Auswertung kardialer MRT-Sequenzen nur von Personen erfolgen sollte, die bereits Erfahrung mit solchen Sequenzen haben. Damit kann eine hohe Reproduzierbarkeit und Sicherheit der Ergebnisse der Auswertungen erreicht werden. Die Auswertung des gRE erscheint anfälliger und bedarf somit besonderer Sorgfalt. Bei der Grenzwertversatilität der Parameter ER und gRE auf einem Philipps-Scanner konnten wir feststellen, dass der Grenzwert von ≥ 2 für die ER beibehalten werden kann. Für das gRE jedoch muss der Grenzwert von ≥ 4,0 auf ≥ 4,5 korrigiert werden. Die Auswertung kardialer MRT-Sequenzen bei Myokarditis ist somit geräteabhängig. Es sollte deswegen eine genaue Evaluation der Grenzwerte für ER und gRE auf den jeweiligen Scannern erfolgen. Jedoch ist auch mit einem Graubereich zwischen 4,0 und 4,5 für das gRE zu rechnen, so dass solche Ergebnisse noch einmal genau geprüft werden müssen. Im akuten Stadium der Myokarditis konnten wir bessere Ergebnisse mit einer MRT-Untersuchung erzielen als im chronischen Stadium. Das gRE schneidet hier besser ab als die ER. Die hier gezeigten Ergebnisse können die diagnostische Sicherheit einer EMB in der Diagnostik einer Myokarditis vielleicht noch nicht ganz erreichen. Jedoch ist auch die EMB als Goldstandard in der Diagnostik einer Myokarditis immer wieder in der Diskussion. Die kardiale MRT ermöglicht eine differenzierte Einschätzung der myokardialen Funktions- und Gewebeeigenschaften und ist somit in Kombination aller MRT-Sequenzen geeignet, Aktivität und Verlauf einer akuten Myokarditis besser einzuschätzen. In der Zukunft wird somit die kardiale MRT als ein nicht-invasives, strahlenfreies Untersuchungsverfahren eine immer größere Rolle in der Diagnostik entzündlicher Herzerkrankungen spielen