Feasibility of Imaging Myelin Lesions in Multiple Sclerosis

The goal of this study was to provide a feasibility assessment for PET imaging of multiple sclerosis (MS) lesions based on their decreased myelin content relative to the surrounding normal-appearing brain tissue. The imaging agent evaluated for this purpose is a molecule that binds strongly and specifically to myelin basic protein. Physiology-based pharmacokinetic modeling combined with PET image simulation applied to a brain model was used to examine whether such an agent would allow the differentiation of artificial lesions 4–10 mm in diameter from the surrounding normal-looking white and gray matter. Furthermore, we examined how changes in agent properties, model parameters, and experimental conditions can influence imageability, identifying a set of conditions under which imaging of MS lesions might be feasible. Based on our results, we concluded that PET imaging has the potential to become a useful complementary method to MRI for MS diagnosis and therapy monitoring

Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18kDa Translocator Protein Radioligand [18F]DPA-714

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [18F]DPA-714 [N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide]. At 1 h after injection, almost fivefold higher levels of [18F]DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [18F]DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S)-PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [18F]DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS

Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis.

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS

Quantitative imaging of white and gray matter remyelination in the cuprizone demyelination model using the macromolecular proton fraction

Macromolecular proton fraction (MPF) has been established as a quantitative clinically-targeted MRI myelin biomarker based on recent demyelination studies. This study aimed to assess the capability of MPF to quantify remyelination using the murine cuprizone-induced reversible demyelination model. MPF was measured in vivo using the fast single-point method in three animal groups (control, cuprizone-induced demyelination, and remyelination after cuprizone withdrawal) and compared to quantitative immunohistochemistry for myelin basic protein (MBP), myelinating oligodendrocytes (CNP-positive cells), and oligodendrocyte precursor cells (OPC, NG2-positive cells) in the corpus callosum, caudate putamen, hippocampus, and cortex. In the demyelination group, MPF, MBP-stained area, and oligodendrocyte count were significantly reduced, while OPC count was significantly increased as compared to both control and remyelination groups in all anatomic structures (p < 0.05). All variables were similar in the control and remyelination groups. MPF and MBP-stained area strongly correlated in each anatomic structure (Pearson's correlation coefficients, r = 0.80-0.90, p < 0.001). MPF and MBP correlated positively with oligodendrocyte count (r = 0.70-0.84, p < 0.01 for MPF; r = 0.81-0.92, p < 0.001 for MBP) and negatively with OPC count (r = -0.69--0.77, p < 0.01 for MPF; r = -0.72--0.89, p < 0.01 for MBP). This study provides immunohistological validation of fast MPF mapping as a non-invasive tool for quantitative assessment of de- and remyelination in white and gray matter and indicates the feasibility of using MPF as a surrogate marker of reparative processes in demyelinating diseases

Standardisierter T1w/T2w-Quotient als Marker für mikrostrukturelle Gewebeschäden bei neurologischen Erkrankungen

Introduction Microstructural tissue damage in neurological disorders is typically measured using advanced magnetic resonance imaging (MRI) techniques, such as diffusion-based or quantitative imaging, that require additional scan time and expertise in post-processing, limiting their feasibility in the clinical routine. The ratio of T1-weighted to T2-weighted images (T1w/T2w ratio) was proposed as an alternative to measure tissue microstructure, as it uses scans typically acquired in clinical routine and has simple post-processing. This dissertation investigates the feasibility of a standardized T1w/T2w ratio method and its sensitivity to microstructural tissue damage in multiple sclerosis (MS) and multiple system atrophy (MSA). Methods In Study I, the standardized and conventional T1w/T2w ratios in the gray and white matter were compared between 47 MS patients and healthy controls (matched for age and sex) and clinical correlates (e.g. lesion load, disease severity) were investigated. Study II investigated longitudinal changes in standardized T1w/T2w ratio in the white matter from the first clinical presentation of 102 MS patients and evaluated its association with cortical thickness and disease activity, defined using the No Evidence of Disease Activity (NEDA-3) criteria. Study III investigated whether standardized T1w/T2w ratio values in the middle cerebellar peduncle differed between 28 MSA patients and healthy controls matched for age and sex. Results The standardized T1w/T2w ratio was shown to reduce variability of white matter values and enhance sensitivity to normal-appearing white matter (NAWM) damage in MS patients (Study I). We showed that NAWM standardized T1w/T2w ratio values did not significantly differ from controls in early MS at first clinical presentation but that these values were significantly associated with increasing lesion volume and decreasing cortical thickness over time, mediated by disease activity (Study II). In MSA we showed that the middle cerebellar peduncle standardized T1w/T2w ratio had a high sensitivity and specificity to classify MSA patients compared to controls (Study III). Conclusions This dissertation demonstrates that the standardized T1w/T2w ratio is a valid and more sensitive marker of microstructural tissue damage compared to the conventional T1w/T2w ratio. Furthermore, the standardized T1w/T2w ratio can be used to investigate microstructural damage in neurological disorders such as MS and MSA, corroborating and expanding on findings from more established measures of microstructural damage, such as diffusion tensor imaging. The standardized T1w/T2w ratio represents an important and promising measure of microstructural damage in settings where additional scan time is limited or for retrospective studies where quantitative or diffusion-based MRI data are not available.Mikrostrukturelle Gewebeschäden bei neurologischen Erkrankungen werden typischerweise mit fortschrittlichen Magnetresonanztomographie-Techniken (MRT) wie diffusionsbasierte oder quantitative Verfahren gemessen, die zusätzliche Scan-Zeit und Expertise in der Nachbearbeitung erfordern, was ihre Durchführbarkeit in der klinischen Routine einschränkt. Das Verhältnis von T1-gewichteten zu T2-gewichteten Bildern (T1w/T2w-Verhältnis) wurde als Alternative zur Messung der Gewebemikrostruktur vorgeschlagen, da es Scans verwendet, die im klinischen Alltag aufgenommen werden und eine einfache Nachbearbeitung ermöglichen. Diese Dissertation untersucht die Durchführbarkeit einer standardisierten T1w/T2w-Ratio-Methode und ihre Sensitivität für mikrostrukturelle Schäden bei Multipler Sklerose (MS) und Multipler Systematrophie (MSA). Methoden In Studie I wurden die standardisierten und konventionellen T1w/T2w-Verhältniswerte in der grauen und weißen Substanz zwischen 47 MS Patienten und gematchten gesunden Kontrollen (gematcht für Alter und Geschlecht) verglichen sowie klinische Korrelate (wie z.B. Läsionslast, Krankheitsschwere) untersucht. Studie II untersuchte longitudinale Veränderungen des standardisierten T1w/T2w-Verhältnisses in der weißen Substanz ab der ersten klinischen Präsentation von 102 MS Patienten und bewertete ihre Assoziation mit der kortikalen Dicke und der Krankheitsaktivität, definiert anhand der “No Evidence of Disease Activity” (keine Hinweise auf Krankheitsaktivität; NEDA-3) Kriterien. In Studie III wurde untersucht, ob sich die standardisierten T1w/T2w-Verhältniswerte im mittleren Kleinhirnstiel zwischen 28 MSA Patienten und für Alter und Geschlecht gematchten gesunden Kontrollen unterscheiden. Ergebnisse Es wurde gezeigt, dass das standardisierte T1w/T2w-Verhältnis die Variabilität der Werte der weißen Substanz reduziert und die Sensitivität für normal erscheinende Schäden der weißen Substanz bei MS Patienten erhöht (Studie I). Wir konnten zeigen, dass sich die Werte des standardisierten T1w/T2w-Verhältnisses der normal erscheinenden weißen Substanz bei der ersten klinischen Präsentation der MS nicht signifikant von denen der Kontrollgruppe unterscheiden, dass diese Werte jedoch signifikant mit dem zunehmenden Läsionsvolumen und der abnehmenden kortikalen Dicke im Laufe der Zeit verbunden sind, was durch die Krankheitsaktivität vermittelt wird (Studie II). Bei MSA zeigten wir, dass das standardisierte T1w/T2w-Verhältnis des mittleren Kleinhirnstiels eine hohe Sensitivität und Spezifität zur Klassifizierung von MSA Patienten im Vergleich zu Kontrollen aufweist (Studie III). Schlussfolgerungen Diese Dissertation zeigt, dass das standardisierte T1w/T2w-Verhältnis ein valider und sensitiverer Marker für mikrostrukturelle Schäden im Vergleich zum konventionellen T1w/T2w-Verhältnis ist. Darüber hinaus kann das standardisierte T1w/T2w-Verhältnis zur Untersuchung mikrostruktureller Schäden bei neurologischen Erkrankungen (MS und MSA) verwendet werden und bestätigt und erweitert die Ergebnisse etablierter Maße für mikrostrukturelle Schäden wie diffusionsbasierte MRT Verfahren. Das standardisierte T1w/T2w-Verhältnis stellt ein wichtiges und vielversprechendes Maß für mikrostrukturelle Gewebeschäden in Situationen dar, in denen zusätzliche Scan-Zeit begrenzt ist oder für retrospektive Studien, in denen quantitative oder diffusionsbasierte MRT-Daten nicht verfügbar sind

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response