Neuroimaging and functional analyses for multiple sclerosis

For neuroimaging studies of multiple sclerosis(MS) lesions, magnetic resonance imaging (MRI) is most useful, while evoked potentials(EPs) are commonly used for functional analyses of neural damage due to MS. This review summarizes the MRI and EP findings in MS. MS lesions are visualized as high signal intensity lesions on T2-weighted images, proton density(PD)-weighted images, and fluid-attenuated inversion recovery(FLAIR) images, while such lesions demonstrate a low signal on T1-weighted images. New MS lesions are usually enhanced by gadolinium-DTPA on T1-weighted images, and the enhancement generally lasts 4 to 8 weeks. In Asian patients with MS, opticospinal MS(Asian-type MS) shows a significantly smaller numbers of brain MRI lesions than conventional MS(Western-type MS), while opticospinal MS shows a significantly higher frequency of the spinal cord atrophy on MRI than conventional MS. EPs are useful for detecting lesions located in certain portions of the central nervous system. MRI is not sensitive enough to detect small lesions in the optic nerves and spinal cord, whereas EPs are sensitive for optic nerve and spinal cord lesions. Thus, combined use of MRI and EPs is required for the diagnosis and the optimal monitoring of disease activity in MS.     

Serum levels of brain-derived neurotrophic factor correlate with the number of T2 MRI lesions in multiple sclerosis

The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.     

Computerised volumetric analysis of lesions in multiple sclerosis using new semi-automatic segmentation software

The paper describes the application of new semi-automatic segmentation software to the task of detection of anatomical structures and lesion an their threedimensional (3D) visualisation in 23 patients with secondary progressive multiple sclerosis (MS). The purpose is to study the correlation between magnetic resonance imaging (MRI) parameters (volumes of plaques and cerebrospinal fluid spaces) and clinical deficits (neurological deficits in the form of EDSS and RFSS scores, and neuropsychological deficits). The software operates in PC/Windows and PC/NeXTstep environments and utilises graphical user interfaces. Quantitative accuracy is measured by performing segmentation of fluid-filled syringes (relative error of 1.5%), and reproducibility is measured by intra- and inter-observer studies (3% and 7% variability, respectively). The mean volumes of MS plaques show significant correlations with the total RFSS scores (p=0.04). Relative intracranial cerebrospinal fluid (CSF) space volumes show statistically significant correlation with EDSS scores (p=0.01). The mean volume of MS plaques shows a significant correlation with the overall neuropsychological deficits (p=0.03). 3D visualisation helps to understand the relationship of lesions to the surrounding brain structures. The use of semiautomatic segmentation techniques is recommended in the clinical diagnosis of MS patients.     

Revised diagnostic criteria of multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) of presumed autoimmune etiology, characterized by localized areas of inflammation, demyelination, axonal loss and gliosis in the brain and spinal cord. Although the clinical presentation and course of the disease are highly variable, several disease types can be recognized, including relapsing–remitting—(RR), primary–progressive—(PP), secondary–progressive—(SP), progressive–relapsing—(PR) MS and clinically-isolated syndrome (CIS). There is no single clinical feature or diagnostic test that is sufficient to diagnose MS, and the diagnosis is mainly a clinical one. Over the years, several sets of criteria have been proposed for the diagnosis of MS, based on the principles of dissemination in space (DIS) and dissemination in time (DIT) of CNS lesions, and the exclusion of other diseases with similar characteristics. With each revision, new diagnostic criteria modified disease definitions and diagnostic thresholds, while aiming at maintaining sensitivity and improving specificity. According to the older Schumacher and Poser criteria, MS can be diagnosed clinically by demonstrating 2 separate attacks (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). The 2001 McDonald criteria and their 2005 revision incorporated defined magnetic resonance imaging (MRI) criteria for DIS and DIT that provided guidance on how to diagnose MS after CIS. The most recent 2010 McDonald criteria simplify requirements for DIS and DIT and may allow for an earlier diagnosis of MS from a single baseline brain MRI if there are both silent gadolinium-enhancing and nonenhancing lesions. Despite these important advances in the diagnosis of MS, some questions still remain regarding the application and the implications of the new criteria in the daily clinical practice and in clinical trials. Most importantly, thorough clinical evaluation and judgment along with careful differential diagnosis still remain the basics in the diagnosis of MS.     

A hybrid approach based on logistic classification and iterative contrast enhancement algorithm for hyperintense multiple sclerosis lesion segmentation

Multiple sclerosis (MS) is a neurodegenerative disease with increasing importance in recent years, in which the T2 weighted with fluid attenuation inversion recovery (FLAIR) MRI imaging technique has been addressed for the hyperintense MS lesion assessment. Many automatic lesion segmentation approaches have been proposed in the literature in order to assist health professionals. In this study, a new hybrid lesion segmentation approach based on logistic classification (LC) and the iterative contrast enhancement (ICE) method is proposed (LC+ICE). T1 and FLAIR MRI images from 32 secondary progressive MS (SPMS) patients were used in the LC+ICE method, in which manual segmentation was used as the ground truth lesion segmentation. The DICE, Sensitivity, Specificity, Area under the ROC curve (AUC), and Volume Similarity measures showed that the LC+ICE method is able to provide a precise and robust lesion segmentation estimate, which was compared with two recent FLAIR lesion segmentation approaches. In addition, the proposed method also showed a stable segmentation among lesion loads, showing a wide applicability to different disease stages. The LC+ICE procedure is a suitable alternative to assist the manual FLAIR hyperintense MS lesion segmentation task.     

A proposal: How to study pro-myelinating proteins in MS

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS. An unmet need in MS is repair i.e.,promoting endogenous regeneration and remyelination after demyelinating inflammatory injury. Remyelination is critical in neuronal preservation and the prevention of clinical progression. There is a good deal of evidence for histological repair and remyelination in MS patients. Repair is driven by several prominent endogenous pro-myelinating proteinsincluding neural cellular adhesion molecule (N-CAM) and brain derived neurotrophic factor (BDNF) among others. To follow changes during acute re-myelination in vivo in MS subjects, non conventional MRI techniques are necessary such as quantitative susceptibility mapping (QSM) that detects the release of Fe from dying oligodendroglial cells and myelin water imaging (MWI) that detects water captured within newly formed myelin.The best time to monitor changes in pro-myelinating proteins and link those changes to imaging evolution is immediately after the acute inflammatory response in MS lesions (gadolinium enhancement [Gd+]) during an intense period of remyelination. We can monitor MS subjects with new Gd + lesions with periodic imaging along with sampling of blood and CSF and determine if myelin formation is linked with increases in pro-myelinating proteins. This would lead to potential therapeutic manipulation with directly administered proteins to promote CNS re-myelination in animal models and in early clinical trials.     

Multiple sclerosis: role of meningeal lymphoid aggregates in progression independent of relapse activity

The emphasis on mechanisms driving multiple sclerosis (MS) symptomatic worsening suggests that we move beyond categorical clinical classifiers such as relapsing–remitting MS (RR-MS) and progressive MS (P-MS). Here, we focus on the clinical phenomenon progression independent of relapse activity (PIRA), which begins early in the disease course. PIRA occurs throughout MS, becoming more phenotypically evident as patients age. The underlying mechanisms for PIRA include chronic-active demyelinating lesions (CALs), subpial cortical demyelination, and nerve fiber injury following demyelination. We propose that much of the tissue injury associated with PIRA is driven by autonomous meningeal lymphoid aggregates, present before disease onset and unresponsive to current therapeutics. Recently, specialized magnetic resonance imaging (MRI) has identified and characterized CALs as paramagnetic rim lesions in humans, enabling novel radiographic–biomarker–clinical correlations to further understand and treat PIRA.     

Volumetric imaging of myelin in vivo using 3D inversion recovery‐prepared ultrashort echo time cones magnetic resonance imaging

Direct myelin imaging is promising for characterization of multiple sclerosis (MS) brains at diagnosis and in response to therapy. In this study, a 3D inversion recovery‐prepared ultrashort echo time cones (IR‐UTE‐Cones) sequence was used for both morphological and quantitative imaging of myelin on a clinical 3 T scanner. Myelin powder phantoms with different myelin concentrations were imaged with the 3D UTE‐Cones sequence and it showed a strong correlation between concentrations and UTE‐Cones signals, demonstrating the ability of the UTE‐Cones sequence to directly image myelin in the brain. Quantitative myelin imaging with multi‐echo IR‐UTE‐Cones sequences show similar T₂* values for a D₂O‐exchanged myelin phantom (T₂* = 0.33 ± 0.04 ms), ex vivo brain specimens (T₂* = 0.20 ± 0.04 ms) and in vivo healthy volunteers (T₂* = 0.254 ± 0.023 ms), further confirming the feasibility of 3D IR‐UTE‐Cones sequences for direct myelin imaging in vivo. In ex vivo MS brain study, signal loss is observed in MS lesions, which was confirmed with histology. For the in vivo study, the lesions in MS patients also show myelin signal loss using the proposed direct myelin imaging method, demonstrating the clinical potential for MS diagnosis. Furthermore, the measured IR‐UTE‐Cones signal intensities show a significant difference between normal‐appearing white matter in MS patients and normal white matter in volunteers, which cannot be found in clinical used T₂‐FLAIR sequences. Thus, the proposed 3D IR‐UTE‐Cones sequence showed clinical potential for MS diagnosis with the capability of direct myelin detection of the whole brain.     

The role of cholesterol metabolism in multiple sclerosis: From molecular pathophysiology to radiological and clinical disease activity

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS leading to demyelination and axonal degeneration. An increasing body of evidence suggests that lipid metabolism is associated with adverse clinical and MRI outcomes in MS. In this review we summarize the findings of association between low-density lipoproteins (LDL), high-density lipoproteins (HDL), their apolipoproteins and oxysterols with clinical and radiological disease activity in MS. Although the causality between disease activity in MS and abnormalities in lipid metabolism has not yet been elucidated, we suggest that advances in this field of research have the potential to improve understanding of MS pathophysiology and the identification of new treatment targets and strategies.     

Radiolabeled annexin V imaging: a useful technique for determining apoptosis in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that involves myelin, oligodendrocytes and axons and culminates in consecutive neuronal death and progressive neurologic disability. Based on magnetic resonance imaging (MRI), neuroaxonal loss in MS results in brain atrophy and has a strong correlation with neurological disability.The newer MR imaging tools seem to be sensitive biomarkers for measuring the pathogenetic processes associated with disease activity and progression. However, they are unable to detect apoptosis in neurodegenerative diseases.Annexin V has a high affinity for phosphatidylserine (PS) that presents on the outer surface of the plasma membrane early on during the onset of apoptosis. Radiolabeled annexin V imaging may reveal the initiation and degree of neuronal apoptosis.We propose that radiolabeled annexin V imaging is a useful modality in determining apoptosis in MS and can assess and monitor the effectiveness of neuroprotective and immunomodulatory therapies on the clinical course of MS.     

Widespread demyelination in the cerebellar cortex in multiple sclerosis

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band-like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS.     

Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligodendrocyte glycoprotein in the common marmoset is a useful preclinical model of multiple sclerosis in which white matter lesions can be well visualized with MRI. In this study we characterized lesion progression with quantitative in vivo MRI (4.7 T; T(1) relaxation time +/- Gd-DTPA; T(2) relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T(1) and T(2) relaxation times; MTR) and histology. The histopathological characterization included axonal density measurements and the numeric quantification of infiltrated macrophages expressing markers for early active [luxol fast blue (LFB) or migration inhibition factor-related protein-14 positive] or late active/inactive [periodic acid Schiff (PAS) positive] demyelinating lesion. MRI experiments were done every two weeks until the monkeys were sacrificed with severe EAE-related motor deficits. Compared with the normal appearing white matter, lesions showed an initial increase in T(1) relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T(1) values, while T(2) initially increased and stabilized thereafter and MTR remained decreased. Gd-DTPA leakage was highly variable throughout the experiment. MRI characteristics of the cortex and (normal appearing) white matter did not change during the experiment. We observed that in vivo MTR values correlated positively with the number of early active (LFB+) and negatively with late active (PAS+) macrophages. Ex vivo MTR and relaxation times correlated positively with the number of PAS-positive macrophages. None of the investigated MRI parameters correlated with axonal density.     

Axonal loss and neurofilament phosphorylation changes accompany lesion development and clinical progression in multiple sclerosis

Neuroaxonal damage and loss are increasingly recognized as disability determining features in multiple sclerosis (MS) pathology. However, little is known about the long-term sequelae of inflammatory demyelination on neurons and axons. Spinal cord tissue of 31 MS patients was compared to three amyotrophic lateral sclerosis (ALS) and 10 control subjects. MS lesions were staged according to the density of KiM-1P positive macrophages and microglia and the presence of myelin basic protein (MBP) positive phagocytes. T cells were quantified in the parenchyma and meninges. Neuroaxonal changes were studied by immunoreactivity (IR) for amyloid precursor protein (APP) and variably phosphorylated neurofilaments (SMI312, SMI31, SMI32). Little T cell infiltration was still evident in chronic inactive lesions. The loss of SMI32 IR in ventral horn neurons correlated with MS lesion development and disease progression. Similarly, axonal loss in white matter (WM) lesions correlated with disease duration. A selective reduction of axonal phosphorylated neurofilaments (SMI31) was observed in WM lesions. In ALS, the loss of neuronal SMI32 IR was even more pronounced, whereas the relative axonal reduction resembled that found in MS. Progressive neuroaxonal neurofilament alterations in the context of chronic inflammatory demyelination may reflect changes in neuroaxonal metabolism and result in chronic neuroaxonal dysfunction as a putative substrate of clinical progression.     

Proton magnetic resonance spectroscopy in primary and secondary progressive multiple sclerosis

The objective of this study was to characterize and compare the proton magnetic resonance spectrum of a voxel, containing lesions or normal-appearing white matter (NAWM), in primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) patients. Single-voxel proton magnetic resonance spectroscopy and magnetic resonance imaging were performed in 35 MS patients (17 PP and 18 SP) and 17 controls. Spectra from an 8 ml voxel located in the parieto-occipital region were obtained with a spin-echo pulse sequence (1600 ms/135 ms/256, TR/TE/acquisitions). Resonance areas due to N-acetylaspartate (NAA), creatine/phosphocreatine (Cr) and choline compounds (Cho) were determined, and results expressed in terms of area in arbitrary units or as metabolite ratios. With respect to the control group, there were significant reductions in NAA and NAA/Cho ratio in the PP-lesion, SP-lesion, PP-NAWM and SP-NAWM groups. There were no significant differences between the PP-NAWM and SP-NAWM groups. These results support the existence of metabolic changes in the white matter of PP and SP patients and suggest that there is neuronal damage and/or loss in both clinical courses. Finally, characterization of the parieto-occipital region showed no significant differences in the spectral pattern of NAWM between PP and SP clinical courses of MS.     

Multicontrast MRI of remyelination in the central nervous system

Although magnetic resonance imaging (MRI) represents the most sensitive tool for the detection of white matter abnormalities in patients with multiple sclerosis (MS), the heterogeneity of MS placques severely hampers the elucidation of specific pathophysiological processes. In order to identify putative MRI markers for de- and remyelination, we employed the cuprizone mouse model which leads to a selective and reversible demyelination of the corpus callosum with little or no axonal damage. Apart from histopathology, animals were studied with high-resolution three-dimensional MRI in vivo using multiple contrasts. While individual MRI findings significantly correlated with electron microscopy, the differentiation of regions with normal, demyelinated or remyelinated white matter by one contrast alone was less specific than by histology or electron microscopy. However, an accurate MRI prediction of the in vivo myelin status was achieved by a discriminant function analysis using a combination of T1, T2 and magnetization transfer contrast. With a correct assignment of 95% of all animals examined, the procedure will allow for the survey of new therapeutic approaches aiming at improved remyelination.     

多种诱发电位和MRI检查在多发性硬化诊断中的价值

目的：探讨诱发电位和磁共振成像（MRI）检查在多发性硬化（MS）诊断中的价值。方法：收集65例MS患者的临床资料、磁刺激运动诱发电位（MEP）、脑干听觉诱发电位（BAEP）、视觉诱发电位（VEP）、体感诱发电位（SEP）以及MRI结果,比较不同检测方法对其临床诊断的价值。结果：MS患者的磁刺激MEP、BAEP、VEP、SEP以及MRI的异常检出率分别为78％（51／65）、51％（33／05）、80％（52／65）、71％（46／65）和85％（55／65）。4项诱发电位检查总异常检出率为88％（57／65）,与MRI检查结果比较差异无统计学意义（P〉0．05）。各种诱发电位和MRI检查均能发现临床下病灶：6例患者经MRI检查发现病灶但无相应临床症状;8例患者有临床症状而MRI检查未见相应病灶,但诱发电位检查可见异常。结论：MRI和各种诱发电位检查具有相互补充作用,结合临床合理选择使用此两种检查有助于提高MS诊断的敏感性。     

磁共振成像、FLAIR序列及弥散加权成像技术对多发性硬化的诊断价值分析

目的比较常规磁共振成像（MRI）、液体衰减反转恢复（FLAIR）序列及弥散加权成像（DWI）检查技术对多发性硬化（MS）的诊断价值。方法58例MS患者，其中男性34例，女性24例，年龄4～70岁，平均年龄35．95岁。使用MRI进行T1加权、T2加权、FIAIR序列及弥散加权成像检查。将4种序列图像进行比较，同时使用软件进行DWI的弥散系数（ADC）及影像分析。结果①FLAIR序列共检出病灶877个，而T1WI、T2WI和DWI分别检出病灶651、776和537个，分别为FLAIR序列检出病灶数的74％、88％和61％。各成像序列对病灶的检出率之间的差异有显著统计学意义（P〈0．0001）。②MS病灶主要分布在脑室周围白质和半卵圆中心区，占总病灶数的96．1％。其中分布在脑室周围白质的病灶数与半卵圆中心区者相比，差异无统计学意义（P〉0．05），而与脑干、小脑和胼胝体相比，差异均有显著统计学意义（均P〈0．01）。③T1WI信号多为低信号、略低信号和等信号，T2WI及FLAIR序列为高信号，DWI在急性期病灶显示为略高信号影，在慢性期可表现为等信号或低信号。④MS急性期病灶平均ADC与急性脑梗死相比差异无统计学意义（P〉0．05）。亚急性和慢性期平均ADC高于脑缺血的ADC（P〈0．001），但低于脑肿瘤的ADC（P〈0．05）。结论对MS病灶的阳性检出率，FLAIR序列优于其余3个序列；DWI可以较好地区分MS病灶分期，同时应用DWI、ADC检查对判别病灶的性质、鉴别诊断有较大帮助，是诊断MS等脱髓鞘疾病的有效影像学方法。     

Wallenberg syndrome: magnetic imaging findings and clinical correlation

Wallenberg's syndrome is one of the most common clinically recognized conditions due to brain stem infarct, which can nowadays be identified by modern neuro-imaging techniques. We describe a patient complaining of miosis, dysphonia, and dysphagia followed by ataxia. An MRI evaluation was performed including diffusion-weighted imaging, apparent diffusion coefficient, T2-weighted images, fluid attenuated inversion recovery (FLAIR) and perfusion. A brief discussion of imaging findings is presented as well as a clinical correlation of the symptoms with the anatomic location of the lesion. This case report emphasizes the importance of imaging findings and their clinical correlation with neurological examination.     

T-cell-mediated disruption of the neuronal microtubule network: correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis

During the course of the central nervous system autoimmune disease multiple sclerosis (MS), damage to myelin leads to neurological deficits attributable to demyelination and conduction failure. However, accumulating evidence has indicated that axonal injury is also a predictor of MS clinical disease. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we examined whether axonal dysfunction occurred early in disease and correlated with disease symptoms. We tracked axons during EAE by using transgenic mice that express yellow fluorescent protein (YFP) in neurons. At the onset of disease, we observed a loss of YFP fluorescence in the spinal cord in areas that coincided with immune cell infiltration, before prominent demyelination. These inflammatory lesions also exhibited evidence of axonal injury but not axonal loss. During the recovery phase of EAE, the return of YFP fluorescence occurred in parallel with the resolution of inflammation. Using in vitro cultured neurons expressing YFP, we demonstrated that encephalitogenic T cells alone directed the destabilization of microtubules within neurites, resulting in a change in the pattern of YFP fluorescence. This study provides evidence that encephalitogenic T cells directly cause reversible axonal dysfunction at the onset of neurological deficits during an acute central nervous system inflammatory attack.