Arbeiten zur Optischen Kohärenztomographie, Magnetresonanzspektroskopie und Ultrahochfeld-Magnetresonanztomographie

Abstrakt (Deutsch) Hintergrund: Die Multiple Sklerose ist eine der häufigsten neurologischen Erkrankungen, die zu Behinderung bereits im jungen Erwachsenenalter führen kann. Hierzu tragen im Krankheitsprozess sowohl neuroinflammatorische wie auch neurodegenerative Komponenten bei. Moderne bildgebende Verfahren wie die Ultrahochfeld-Magnetresonanztomographie (UHF-MRT), die Optische Kohärenztomographie (OCT) und die Magnetresonanzspektroskopie (MRS) können benutzt werden, um diese neurodegenerativen Prozesse näher zu charakterisieren und im zeitlichen Verlauf zu beobachten. Zielsetzung: Ziel ist es, die genannten Verfahren zur Charakterisierung von Kohorten von MS-Patienten einzusetzen und die Verfahren zueinander, sowie mit klinischen Parametern in Beziehung zu setzen oder diagnostisch zu nutzen. Methodik: Patienten mit Multipler Sklerose oder Neuromyelitis optica wurden klinisch-neurologisch, mit Optischer Kohärenztomographie, Sehprüfungen, Untersuchungen der visuell evozierten Potentiale (VEP), (Ultrahochfeld-) Magnetresonanztomographie und Magnetresonanzspektroskopie untersucht. Ergebnisse: Die in der Studie eingesetzten bildgebenden Verfahren konnten dazu beitragen, Neuroinflammation und Neurodegeneration bei an Multiple Sklerose erkrankten Patienten näher zu charakterisieren. So steht eine mittels OCT messbare Verdünnung retinaler Nervenfaserschichten (RNFL) in Zusammenhang mit dem per MRT gemessenen Hirnparenchymvolumen und Neurodegeneration anzeigenden Parametern, die mithilfe der Magnetresonanzspektroskopie untersucht wurden. Mithilfe der UHF-MRT konnte ein Zusammenhang zwischen dem Volumen und der entzündlichen Läsionslast der Sehstrahlung, der RNFL-Dicke, VEP-Latenzen und Einschränkungen des Sehvermögens dargestellt werden. Außerdem ließen sich mit der UHF-MRT auch neurogenerative Aspekte im Sinne von bleibenden Parenchymdefekten innerhalb entzündlicher Läsionen und einer Verschmächtigung der Sehstrahlung nachweisen und die Detektion insbesondere kortikaler MS-Läsionen wurde im Vergleich zur konventionellen MRT verbessert. Zusammenfassung: OCT, MRS und UHF-MRT sind Verfahren, die eine genauere Beschreibung von Neuroinflammation und Neurodegeneration bei MS-Patienten ermöglichen, wie hier vor allem für die Sehbahn gezeigt wurde. Sie sind nichtinvasiv und lassen sich zur näheren Charakterisierung des aktuellen Zustandes und zur Beobachtung des Krankheitsverlaufs von MS-Patienten benutzen.Abstract (English) Background: Multiple sclerosis (MS) is the most common disabling neurologic disease, that causes impairment in younger people. Both neuroinflammatory and neurodegenerative processes contribute to the pathogenesis of multiple sclerosis. Innovative imaging methods, such as ultra-high field magnetic resonance tomography (UHF-MRI), optic coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) can be used for characterizing these neurodegenerative processes in detail and over time course. Objective: To use the imaging methods mentioned above to further characterize cohorts of MS patients and to correlate the parameters with themselves as well as with clinical parameters and to evaluate their prognostic and diagnostic relevance. Methods: Patients with multiple sclerosis were examined clinically, by OCT, visual acuity testing, examination of visually evoked potentials, ultra high field magnetic resonance tomography and magnetic resonance spectroscopy. Results: The imaging methods used in these studies contributed to further characterize neuroinflammation und neurodegeneration in multiple sclerosis patients. A thinning of the retinal nerve fiber layer (RNFL) is correlated with brain parenchyma volume measured by MRI, and markers indicating ongoing neurodegenerative processes as detected by MRS. Using UHF-MRI, a correlation between optic radiation properties (such as inflammatory lesion load and its volume) and RNFL thickness, VEP latencies and visual impairment could be demonstrated. Furthermore, UHF-MRI demonstrated neurodegenerative aspects such as parenchymal defects within inflammatory lesions, an optic radiation thinning and allowed a more precise detection of MS lesions than conventional MRI, in particular cortical grey matter lesions. Summary: OCT, MRS and UHF-MRI are feasible methods to provide a more detailed description of neuroinflammation and neurodegeneration in MS patients, as demonstrated in these studies particularly for the visual pathway. They are non-invasive and can be utilized for clinical to study the disease course and also in differential diagnostic procedures

Brain Viscoelasticity Alteration in Chronic-Progressive Multiple Sclerosis

Introduction: Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS

MRI Pattern Recognition in Multiple Sclerosis Normal-Appearing Brain Areas

Objective Here, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing­remitting type) in lesioned areas, areas of normal­appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques. Methods A lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information. Results Among regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10−13). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10−7). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10−10). Interpretation We identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale

Reduction of brain parenchymal viscoelastic constants.

<p>MS patients present with significantly reduced brain parenchymal elasticity <i>μ</i> (<b>a</b>, P<0.001), but also with a reduction in the powerlaw exponent <i>α</i> (<b>b</b>, P<0.001) in MS patients with progressive disease course. The boxplot depicts the lower and upper quartiles as well as the 50^th percentile (median). Full data range is presented by the whiskers. sp – secondary progressive, pp – primary progressive, rr – relapsing remitting; *data for rr-MS are taken from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029888#pone.0029888-Wuerfel1" target="_blank">[14]</a> and reprocessed according to the methods reported in herein.</p

Brain atrophy in MS patients.

<p>Significantly reduced brain parenchymal volume (<b>a</b>) and brain parenchymal fraction (BPF) (<b>b</b>) in MS patients compared to matched healthy individuals (*** P<0.001). The boxplots depict the lower and upper quartiles as well as the 50^th percentile (median). Full data range is presented by the whiskers. sp – secondary progressive, pp – primary progressive, rr – relapsing remitting.</p

Viscoelastic constants for the detection of brain pathology.

<p>Individual data of shear elasticity <i>μ</i> and powerlaw exponent <i>α</i> of brain tissue in healthy volunteers and MS patients. The areas under the receiver characteristics curve (AUROC) for separating healthy volunteers from MS patients are 0.896 and 0.936 for <i>μ</i> and <i>α</i>, respectively.</p

Demographical data, clinical characteristics, brain volumes, brain parenchymal fraction (BPF) and viscoelastic constants <i>μ</i> and <i>α</i> according to the springpot model.

<p>MS – multiple sclerosis; sp – secondary progressive; pp – primary progressive; rr – relapsing remitting; EDSS – expanded disability status scale; n.a. – not applicable; standard deviations are given in brackets;</p><p>*data taken from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029888#pone.0029888-Wuerfel1" target="_blank">[14]</a> and processed corresponding to the data of progressive MS.</p

Scheme of cerebral multifrequency MRE.

<p><b>a:</b> The MRI scanner is combined with a device for acoustical head stimulations comprising: 1) a signal generator that produces a multifrequency signal composed from four harmonic frequencies of 25, 37.5, 50 and 62.5 Hz; 2) a loudspeaker for generating acoustic vibrations; 3) an extended piston that transfers the vibrations into the scanner and 4) a head cradle for stimulating head vibrations mainly along the head-feet direction. <b>b:</b> A single-shot echo planar imaging (EPI) sequence is sensitized to harmonic motions by a 60-Hz sinusoidal motion encoding gradient (MEG) of four cycles and directed through-plane. The image planes are positioned in transverse orientation through the brain (parallel to the “anterior and posterior commissure line (AC-PC)”) in a central slab of the brain. The resulting wave images display the motion component along the head-feet direction corresponding to the major vibration direction of the actuator. <b>c:</b> Image processing comprises Fourier decomposition of the superposed oscillations yielding four complex single-frequency wave images, corresponding to the experimentally applied vibration frequencies. Each of the wave images is separately inverted, resulting in four complex-valued shear modulus images, whose values are averaged within a region of interest comprising the parenchyma within the image slice (demarcated in the wave images by white lines).</p

Optical Coherence Tomography.

<p>Differences in retinal optical coherence tomography measurements between HNPP patients (in red) and healthy controls (HC, in grey). A) Peripapillary retinal nerve fiber layer thickness (pRNFL), B) pRNFL in the papulomacular bundle (PMB), C) pRNFL in the nasal hemisphere, D) total macular volume (TMV), E) ganglion cell and inner plexiform layer (GCIP), F) inner nuclear layer (INL). P values are derived from generalized estimating equation models.</p

A Randomized, Placebo-Controlled Trial

Objective: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. Results: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. Conclusion: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. Classification of Evidence This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI