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

Computational modelling of imaging markers to support the diagnosis and monitoring of multiple sclerosis

Multiple sclerosis is a leading cause of neurological disability in young adults which affects more than 2.5 million people worldwide. An important substrate of disability accrual is the loss of neurons and connections between them (neurodegeneration) which can be captured by serial brain imaging, especially in the cerebral grey matter. In this thesis in four separate subprojects, I aimed to assess the strength of imaging-derived grey matter volume as a biomarker in the diagnosis, predicting the evolution of multiple sclerosis, and developing a staging system to stratify patients. In total, I retrospectively studied 1701 subjects, of whom 1548 had longitudinal brain imaging data. I used advanced computational models to investigate cross-sectional and longitudinal datasets. In the cross-sectional study, I demonstrated that grey matter volumes could distinguish multiple sclerosis from another demyelinating disorder (neuromyelitis optica) with an accuracy of 74%. In longitudinal studies, I showed that over time the deep grey matter nuclei had the fastest rate of volume loss (up to 1.66% annual loss) across the brain regions in multiple sclerosis. The volume of the deep grey matter was the strongest predictor of disability progression. I found that multiple sclerosis affects different brain areas with a specific temporal order (or sequence) that starts with the deep grey matter nuclei, posterior cingulate cortex, precuneus, and cerebellum. Finally, with multivariate mechanistic and causal modelling, I showed that brain volume loss causes disability and cognitive worsening which can be delayed with a potential neuroprotective treatment (simvastatin). This work provides conclusive evidence that grey matter volume loss affects some brain regions more severely, can predict future disability progression, can be used as an outcome measure in phase II clinical trials, and causes clinical and cognitive worsening. This thesis also provides a subject staging system based on which patients can be scored during multiple sclerosis

Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data

Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials

Occasional essay: upper motor neuron syndrome in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) requires recognition of both lower (LMN) and upper motor neuron (UMN) dysfunction.1 However, classical UMN signs are frequently difficult to identify in ALS.2 LMN involvement is sensitively detected by electromyography (EMG)3 but, as yet, there are no generally accepted markers for monitoring UMN abnormalities,4 the neurobiology of ALS itself, and disease spread through the brain and spinal cord,.5 Full clinical assessment is therefore necessary to exclude other diagnoses and to monitor disease progression. In part, this difficulty regarding detection of UMN involvement in ALS derives from the definition of ‘the UMN syndrome’. Abnormalities of motor control in ALS require reformulation within an expanded concept of the UMN, together with the neuropathological, neuro-imaging and neurophysiological abnormalities in ALS. We review these issues here

mr imaging of gray matter involvement in multiple sclerosis implications for understanding disease pathophysiology and monitoring treatment efficacy

SUMMARY: Recent pathologic and MR imaging studies have challenged the classic view of MS as a chronic inflammatory-demyelinating condition affecting solely the WM of the central nervous system. Indeed, an involvement of the GM has been shown to occur from the early stages of the disease, to progress with time, and to be only moderately correlated with the extent of WM injury. In this review, we summarize how advances in MR imaging technology and methods of analysis are contributing to ameliorating the detection of focal lesions and to quantifying the extent of "occult" pathology and atrophy, as well as to defining the topographic distribution of such changes in the GM of patients with MS. These advances, combined with the imaging of brain reorganization occurring after tissue injury, should ultimately result in an improved understanding and monitoring of MS clinical manifestations and evolution, either natural or modified by treatment. Cereb : cerebellum Cho : choline CIS : clinically isolated syndromes DIR : double inversion recovery DTI : diffusion tensor imaging EDSS : Expanded Disability Status Scale FA : fractional anisotropy FLAIR : fluid-attenuated inversion recovery fMRI : functional MR imaging GM : gray matter L : left MD : mean diffusivity MS : multiple sclerosis MT : magnetization transfer MTR : magnetization transfer ratio NAA : N -acetylaspartate NAWM : normal-appearing white matter PM : premotor cortex PPMS : primary-progressive MS R : right RRMS : relapsing-remitting MS RT : relaxation time SII : secondary sensorimotor cortex SMA : supplementary motor area SMC : sensorimotor cortex SPM : statistical parametric mapping SPMS : secondary-progressive MS Thal : thalamus WM : white matte