Quantitative Susceptibility Mapping: Contrast Mechanisms and Clinical Applications.

Quantitative susceptibility mapping (QSM) is a recently developed MRI technique for quantifying the spatial distribution of magnetic susceptibility within biological tissues. It first uses the frequency shift in the MRI signal to map the magnetic field profile within the tissue. The resulting field map is then used to determine the spatial distribution of the underlying magnetic susceptibility by solving an inverse problem. The solution is achieved by deconvolving the field map with a dipole field, under the assumption that the magnetic field is a result of the superposition of the dipole fields generated by all voxels and that each voxel has its unique magnetic susceptibility. QSM provides improved contrast to noise ratio for certain tissues and structures compared to its magnitude counterpart. More importantly, magnetic susceptibility is a direct reflection of the molecular composition and cellular architecture of the tissue. Consequently, by quantifying magnetic susceptibility, QSM is becoming a quantitative imaging approach for characterizing normal and pathological tissue properties. This article reviews the mechanism generating susceptibility contrast within tissues and some associated applications

Cerebrospinal Fluid Analysis in Multiple Sclerosis Diagnosis: An Update

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with brain neurodegeneration. MS patients present heterogeneous clinical manifestations in which both genetic and environmental factors are involved. The diagnosis is very complex due to the high heterogeneity of the pathophysiology of the disease. The diagnostic criteria have been modified several times over the years. Basically, they include clinical symptoms, presence of typical lesions detected by magnetic resonance imaging (MRI), and laboratory findings. The analysis of cerebrospinal fluid (CSF) allows an evaluation of inflammatory processes circumscribed to the CNS and reflects changes in the immunological pattern due to the progression of the pathology, being fundamental in the diagnosis and monitoring of MS. The detection of the oligoclonal bands (OCBs) in both CSF and serum is recognized as the “gold standard” for laboratory diagnosis of MS, though presents analytical limitations. Indeed, current protocols for OCBs assay are time-consuming and require an operator-dependent interpretation. In recent years, the quantification of free light chain (FLC) in CSF has emerged to assist clinicians in the diagnosis of MS. This article reviews the current knowledge on CSF biomarkers used in the diagnosis of MS, in particular on the validated assays and on the alternative biomarkers of intrathecal synthesis

Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.

BackgroundTherapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.AimsWe aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.Materials and methodsActive EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed.ResultsProphylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers.DiscussionEven when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.ConclusionsOur results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression

Backward Walking: A Novel Marker Of Fall Risk, Cognitive Dysfunction, And Myelin Damage In Persons With Multiple Sclerosis

Multiple sclerosis (MS) is a progressive, neurologic disease of the central nervous system that causes debilitating motor, sensory and cognitive impairments. As a result, persons with MS are at an increased risk for falls and falls represent a serious public health concern for the MS population. The current clinical measures used to assess fall risk in MS patients lack sensitivity and predictive validity for falls and are limited in their ability to capture to multiple functional domains (i.e., motor, sensory, cognitive and pathological domains) that are impaired by MS. Backward walking sensitively detects falls in the elderly and other neurologic diseases. However, backward walking and falls has never been explored in the MS population and the underlying reasons as to why backward walking sensitively detects falls remains unknown. Identification of a quick, simply and clinically feasible fall risk measures related to multiple functions impacted by MS and related to fall risk, which can detect falls before they occur is critical for fall prevention and timely and targeted intervention. Therefore, this dissertation examines backward walking as a novel marker of fall risk and its cognitive and pathological underpinnings to support its clinical utility. Our results indicate that backward walking is a sensitive marker of fall risk in the MS population, regardless of co-morbid cognitive deficits, and that examining underlying brain regions likely to contribute to backward walking performance including the corticospinal tract, corpus callosum and cerebellum, with neuroimaging tools sensitive to myelin (i.e., Myelin Water Imaging) demonstrate potential to identify underlying mechanisms of backward walking performance in the MS population. This work is the critical first step in establishing backward walking as a sensitive marker of fall risk for the MS population and leads the way to more personalized fall prevention therapies and interventions to improve clinical outcomes and decrease fall rates in the MS population

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis

Imaging; Multiple sclerosis; Quantitative MRIImatges; Esclerosi múltiple; Ressonància magnètica quantitativaImágenes; Esclerosis múltiple; Resonancia magnética cuantitativaQuantitative 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.C.G. is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E! 113682 HORIZON2020. F.B. is supported by the National Institute for Health Research biomedical research center at University College London Hospitals. J.W. is supported by the EU Horizon2020 research and innovation grant (FORCE, 668039). D.S.R. is supported by the Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health. A.T.T. is supported by an Medical Research Council grant (MR/S026088/1). S.R. is supported by the Austrian Science Foundation (FWF) grant I-3001. P.S. is supported by the Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health. H.V. is supported by the Dutch multiple sclerosis Research Foundation, ZonMW and HealthHolland

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