Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis

Abstract. Magnetic resonance (MR) techniques are of value in following the pathological process of multiple sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment. However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the normal appearing white matter (NAWM) and grey matter (NAGM). Quantitative structural MR techniques, including measures of magnetisation transfer, diffusion, relaxation times and spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM. These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load. Furthermore, functional MRI (fMRI) studies of motor and visual paradigms has identified a range of responses suggesting that cortical plasticity exists; such modified responses are seen in the earliest stages of disease and in the absence of visible lesions, but are more pronounced with disease progression and increasing lesion load and abnormality in the NAWM. Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short. Whilst existing quantitative MR measures from normal appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS, none of them fully or even predominantly accounts for the patients functional state nor can be relied on as a definitive surrogate measure of treatment effect. Better resolution of the abnormalities is needed especially in grey matter where pathological foci are known to be abundant. Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the normal appearing tissues. In future, new imaging modalities are needed that provide a more specific measure of histopathological and cellular aspects of the disease process in vivo.     

Magnetic resonance imaging in patients with multiple sclerosis and spinal cord involvement: 28 cases

In patients with clinically isolated spinal disease, magnetic resonance imaging (MRI) provides a non-invasive method of detecting surgically treatable causes and is also useful in detecting asymptomatic brain lesions where the cord syndrome is due to multiple sclerosis (MS). We report the findings of spinal and brain MRI in 28 patients with spinal cord disorder due to MS. It was possible to detect intrinsic plaques reliably in the majority of patients (60.7%) with clinical findings of spinal cord MS. The results of MRI are compared with the clinical status and with cerebrospinal fluid findings and evoked potentials.     

Abnormal ubiquitination of axons in normally myelinated white matter in multiple sclerosis brain

The hallmark of the lesions in multiple sclerosis (MS) is inflammatory demyelination with sparing of axons. Recent neuropathological and neuroradiological investigations show that structural changes of the axons occur, both in plaques and in the normal appearing white matter. A better understanding of the axonal damage in MS is important, since this may be responsible for permanent disability. We have investigated the immunoreactivity for ubiquitin, a sensitive method to detect axonal dystrophy and accumulation of abnormal proteins in pathological conditions of the nervous system, in the brains of six cases of MS (age range 39-66 years). Tissue blocks were fixed in formalin and embedded in paraffin. A panel of antibodies was used: anti-ubiquitin, anti-neurofilament (SMI-31 + SMI-32), anti-amyloid precursor protein and anti-PGP9.5. We focused our attention on chronic plaques, recognized by the absence of Luxol Fast Blue B-positive inclusions in macrophages. SMI-31 + SMI-32 showed the presence of a variable amount of axons within the plaques; the axonal network within the plaques was looser than outside. No ubiquitin reactivity was present in chronic plaques. In the normally myelinated white matter surrounding the plaques, a dense granular ubiquitin immunoreactivity was found both near and far from the plaque edge. No similar staining was found in control brains. Ubiquitination is the first step of a non-lysosomal degradation pathway of proteins. The present findings suggest a derangement of this proteolytic pathway in the axons outside the plaques, possibly as a consequence of chronic absence of myelin in the axonal segment inside the plaque. The spectrum of axonal changes in MS appears to be wider than expected and involves the apparently normal white matter.     

Magnetic resonance imaging in multiple sclerosis: the role of conventional imaging

Magnetic resonance imaging (MRI) of the brain and spinal cord plays a central role in establishing the diagnosis of multiple sclerosis (MS), in monitoring disease activity, and as a key outcome measure in clinical trials of new MS therapies. Conventional MRI continues to evolve, reflecting advances in imaging hardware and software. These advances have led to important new insights into MS disease pathophysiology and can be used to improve patient management. Despite these improvements, standard MRI continues to capture only a small portion of the underlying changes that occur during the course of the disease.     

Magnetic resonance imaging as a tool to examine the neuropathology of multiple sclerosis

Magnetic resonance imaging (MRI) has significantly extended the understanding of multiple sclerosis (MS), owing to its ability to sensitively depict the dynamics of the disease process in vivo. The subject of this review is the use of MRI in the post-mortem setting, with emphasis on how it may be used to improve the specimen selection process at autopsy. Lesions with active demyelination are highly interesting in the study of MS pathogenesis, but are rare in a typical autopsy material of chronic MS. The yield of MS lesions in autopsy specimen selection can be increased by the use of MRI-guided tissue sampling, as a significant proportion of abnormalities detected by post-mortem MRI are not macroscopically visible/palpable. The majority of these MRI abnormalities have been found to represent either discrete areas of microglial activation with no demyelination (so-called (p)reactive lesions), or active demyelinating MS lesions by further histopathological examination. The presence and extent of MS pathology outside of the focal demyelinated lesions is more readily appreciated by MRI-guided specimen sampling, as has been shown in the study of extensive areas of partial myelin loss in the spinal cord. A further advantage of MRI-guided specimen sampling is the ability to use three-dimensional and quantitative measures. The potential of correlating these with histopathological data may be further exploited in the future. The technical procedure for MRI-guided tissue sampling at autopsy is presented, and the limitations of the technique are discussed.     

Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetisation transfer study

BACKGROUND: Patients with primary progressive multiple sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional magnetic resonance imaging (MRI). This may relate to diffuse pathological processes occurring in normal appearing brain tissue (NABT) involving both white matter (NAWM) and grey matter (NAGM). Magnetisation transfer imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS. AIM: To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS. METHODS: We studied 43 patients within 5 years of disease onset and 43 controls. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored. Magnetisation transfer ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles. Proton density, T2, T1, and gadolinium enhancing lesion loads were also calculated. RESULTS: Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < or = 0.001). Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM. CONCLUSION: MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability. NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.     

1H Magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. ¹H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86–1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27–2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62–10.38 mM; controls, median 7.77 mM, range 6.60–9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group. Received: 22 January 1999 Received in revised form: 11 June 1999 Accepted: 16 June 1999     

脊髓型多发性硬化临床诊断分析

目的 总结分析脊髓型多发性硬化(MS)的临床特点和MRI表现.方法 回顾性分析21例脊髓型MS的临床特点和MRI表现,所有患者行脊髓和颅脑MRI检查.结果 脊髓型MS除有脊髓病变的临床表现外,临床症状和体征的多样性是其特点,如感觉障碍、肢体无力、视力障碍等;脊髓内病灶的MRI特点是不规则斑片状和条带状异常信号,位于脊髓两侧和后部,在T:WI像上为高或稍高信号,在T1WI上为等信号或稍低信号;80.9%(17/21)脊髓型MS合并脑内病灶.结论 脊髓型MS临床表现呈多样性,MRI可以准确显示脊髓内病灶,颅脑MRI检查有助于脊髓型MS的诊断.     

Autonomic dysfunction in multiple sclerosis: cervical spinal cord atrophy correlates

Autonomic dysfunction has rarely been studied in patients suffering from multiple sclerosis (MS). Some hypotheses have concerned the pathophysiology, especially with regard to a possible spinal cord origin. However, there have been no previous studies on autonomic dysfunction in MS and spinal cord lesions. This study assessed the frequency of autonomic dysfunction (AD) in MS and the correlation to spinal cord magnetic resonance imaging (MRI) findings. We prospectively studied 75 MS patients (25 with relapsing-remitting forms, 25 with secondary progressive forms and 25 with primary progressive forms). We performed sympathetic skin response, R-R interval variability and orthostatic hypotension testing. Spinal cord MRI was performed to detect demyelinating lesions (sagittal and axial plane) or spinal cord atrophy. Clinical and laboratory evidence of AD was found in 84 % and 56 % of MS patients, respectively. The correlation of the latter with disability was evaluated using the Extended Disability Status Scale. AD was more frequent in primary progressive MS than in the other two forms. AD was correlated with spinal cord cross-sectional area reduction but not with spinal cord hyperintensities. This study confirms that the frequency of AD in MS, especially in primary progressive forms, has until now been underestimated. Furthermore, AD appears to be more closely related to axonal loss, as demonstrated by spinal cord atrophy, than to demyelinating lesions. Received: 20 March 2000, Received in revised form: 13 October 2000, Accepted: 29 October 2000     

多发性硬化患者颈髓扩散张量成像研究

目的 通过扩散张量成像研究多发性硬化患者常规MRI表现正常脊髓(NASC)的改变,并探讨其临床应用价值.方法 采用平面回波成像技术对13 例多发性硬化患者和13 例健康志愿者施行颈髓扩散张量成像检查,分别测量第2 ~ 5 颈椎(C2 ~ 5)水平前索、后索、侧索及灰质兴趣区的部分各向异性(FA)值及平均扩散率(MD)值,比较两组之间所存在的差异性;相关分析检验多发性硬化组患者FA值和MD 值与扩展残疾状态量表(EDSS)评分之间的关系.结果 与正常对照组相比,多发性硬化组患者C2 ~ 5 前索、侧索、后索和灰质NASC 的FA 值降低、MD 值升高(均P < 0.05);相关分析显示,FA 值与EDSS 评分呈负相关(r = - 0.328 ~ - 0.207,P = 0.001 ~ 0.035),各兴趣区MD 值与EDSS 评分呈正相关(r =0.234 ~ 0.409,P = 0.000 ~ 0.018).结论 多发性硬化患者常规MRI 表现比正常脊髓的FA 值降低,提示存在隐匿性病变.脊髓扩散张量成像对多发性硬化患者临床评价和疗效判断有一定应用价值.     

Cervical cord FMRI abnormalities differ between the progressive forms of multiple sclerosis

Objective: Aim of this study was to compare tactile‐associated cervical cord fMRI activity between primary progressive (PP) and secondary progressive (SP) MS patients and to investigate whether cord recruitment was associated with structural brain and cord damage. Experimental Design: Cervical cord fMRI during a tactile stimulation of the right hand was acquired from 17 healthy controls, 18 SPMS patients, and 16 PPMS patients. Average fMRI activity and its topographical distribution in cord sectors (left vs. right, posterior vs. anterior) were assessed. Correlations between cord recruitment and structural cord and brain MRI were estimated. Principal Observations: Progressive MS patients showed an increased cord recruitment compared with controls (P = 0.003). Despite a similar structural cord damage, cord activity was increased in SPMS compared to PPMS patients (P = 0.05). Regional analysis showed a non‐lateralized pattern of cord recruitment in MS patients. Compared to PPMS, SPMS patients had grey matter (GM) atrophy in several cortical and subcortical regions. In SPMS patients, atrophy of the left postcentral gyrus was correlated with cord activity (r = ?0.48, P = 0.04). Conclusions: Patients with progressive MS had an over‐recruitment of the cervical cord, which was more pronounced in SPMS than PPMS, despite similar cord structural damage. The alteration of the complex modulation of spinal cord interneurons possibly due to a loss of supratentorial inhibition secondary to brain injury might contribute to explain the observed functional cord abnormalities. Hum Brain Mapp 33:2072–2080, 2012. © 2011 Wiley Periodicals, Inc.     

视神经脊髓炎脊髓磁共振成像特征

目的 比较视神经脊髓炎(NMO)与多发性硬化(MS)的脊髓MRI特点,从MBI的角度重新认识NMO.方法 对20例MS患者和23例NMO患者的脊髓MRI进行同顾性分析.结果 NMO患者脊髓MRI多表现为线样延髓征、线样延髓脊髓征、线样脊髓征、脊髓横贯性或次横贯性损伤,且常超过3个节段(23例),而MS患者脊髓MRI病变节段短(≥3个节段者8例,χ2=19.142,P<0.01),常呈偏心性分布(17例,与NMO组比较,χ2=25.256,P<0.01).结论 NMO不同于MS,在MRI方面,病灶的分布有其自身特征,而MS的脊髓病灶与髓鞘走向一致.因此,我们从影像学角度进一步证实NMO是有异于MS的一种独立的疾病.     

Magnetization transfer imaging of multiple sclerosis

While conventional magnetic resonance imaging (MRI) measures signal primarily from the hydrogen nuclei of water, magnetization transfer (MT) MRI indirectly detects macromolecular associated hydrogen nuclei via their magnetic interaction with the observable water. In the normal adult CNS, white matter exhibits the largest MT effect due to the macromolecular content of the highly structured and lipid rich myelin. Pathologies which alter the structural integrity and the relative macromolecular-water composition, such as multiple sclerosis (MS), therefore show abnormal MT. Conventional MRI, which has a high MS lesion detection sensitivity but poor specificity in terms of differentiating the pathological state of a plaque, can thus be supplemented by MT to provide more specific information on the extent of demyelination and axonal loss. In this paper we review the basic concepts of MT imaging and its role in MS lesion characterization.Financial support was provided by the Medical Research Council of Canada, Fonds de la Recherche en Santé du Québec, and the Killam Foundation.     

脊髓型多发性硬化的MRI表现

目的总结分析脊髓型多发性硬化的MRI表现。方法搜集经临床证实的脊髓型多发性硬化11例,均行MRI检查,对其临床及MRI资料进行回顾性分析。结果脊髓型多发性硬化的特征性MRI表现为,11例患者的病灶以颈髓多见,病变脊髓在T1WI像为低或等信号,T2WI像为高信号,病灶位于脊髓两侧和后部,病灶活动期呈斑片状或边缘强化,应用糖皮质激素试验性治疗对脊髓出现的可疑脱髓鞘病灶者有一定的帮助。结论脊髓型多发性硬化有其特征性MRI表现,MRI有助于脊髓型多发性硬化的诊断,是目前诊断脊髓型多发性硬化最敏感的影像学方法 。     

Magnetic resonance imaging of spinal cord lesions in multiple sclerosis.

The clinical and pathological manifestations of multiple sclerosis are due to areas of demyelination which occur throughout the white matter of the central nervous system. MRI of the brain frequently shows abnormalities in the hemispheric subcortical white matter; these are demonstrable in the majority of patients and support the clinical diagnosis of multiple sclerosis. Our studies have shown that while MRI identifies such cerebral lesions in nearly all clinically definite multiple sclerosis patients with illness of duration greater than 10 years, these areas of abnormal T2 signal are present less often in the brains of patients studied within 3 years of disease onset. However, symptoms referable to the long tracts of the spinal cord are prominent in many of these patients. Imaging of the spinal cord has presented technical problems because of the small size of the cord, patient body, heart and respiratory movements, and limitations of surface coil technology. The spinal cord of 77 patients with multiple sclerosis have been imaged, revealing three types of abnormalities: (1) approximately half the cords show regions of abnormal T2 weighted signal; (2) during acute exacerbation, spinal cord enlargement (swelling) may be observed; (3) spinal cord atrophy (narrowing) is found particularly in patients with disease of longer duration and greater disability. Unlike the presence of brain lesions, the existence of spinal cord lesions of high T2 signal is not associated with increasing duration of disease but is correlated with disability status. Of patients with such lesions about one fifth did not exhibit brain lesions discernible by MRI.     

A spinal cord MRI study of benign and secondary progressive multiple sclerosis

This study was performed to achieve a better definition of the nature of the disability in multiple sclerosis (MS). Axial spinal cord magnetic resonance imaging (MRI) at C5 was obtained in 15 patients with benign MS, 17 patients with secondary progressive MS and 10 healthy controls. Patients with secondary progressive MS had smaller spinal cord cross-sectional area (P = 0.01) and transverse diameter (P = 0.006) than patients with benign MS. The degree of disability was inversely correlated with both the cross-sectional area (r = –0.6,P = 0.0018) and transverse diameter (r = –0.5,P = 0.0032) of the cord. Spinal cord atrophy was found in 7 (41%) patients with secondary progressive MS and in 2 (13%) with benign MS. These findings suggest that destructive pathology within MS lesions might play a relevant role in the development of disability in MS.     

Pathophysiology of multiple sclerosis damage and repair: Linking cerebral hypoperfusion to the development of irreversible tissue loss in multiple sclerosis using magnetic resonance imaging

Background and purpose

Reduced cerebral perfusion has been observed in multiple sclerosis (MS) and may contribute to tissue loss both acutely and chronically. Here, we test the hypothesis that hypoperfusion occurs in MS and relates to the presence of irreversible tissue damage.

Methods

In 91 patients with relapsing MS and 26 healthy controls (HC), gray matter (GM) cerebral blood flow (CBF) was assessed using pulsed arterial spin labeling. GM volume, T1 hypointense and T2 hyperintense lesion volumes (T1LV and T2LV, respectively), and the proportion of T2-hyperintense lesion volume that appears hypointense on T1-weighted magnetic resonance imaging (T1LV/T2LV) were quantified. GM CBF and GM volume were evaluated globally, as well as regionally, using an atlas-based approach.

Results

Global GM CBF was lower in patients (56.9 ± 12.3 mL/100 g/min) than in HC (67.7 ± 10.0 mL/100 g/min; p < 0.001), a difference that was widespread across brain regions. Although total GM volume was comparable between groups, significant reductions were observed in a subset of subcortical structures. GM CBF negatively correlated with T1LV (r = −0.43, p = 0.0002) and T1LV/T2LV (r = −0.37, p = 0.0004), but not with T2LV.

Conclusions

GM hypoperfusion occurs in MS and is associated with irreversible white matter damage, thus suggesting that cerebral hypoperfusion may actively contribute and possibly precede neurodegeneration by hampering tissue repair abilities in MS.     

Magnetic resonance imaging findings in 22 cases of myelitis: comparison between patients with and without multiple sclerosis

We reviewed the magnetic resonance imaging (MRI) database of the Dent Neurologic Institute to study the abnormal findings in myelitis. We identified 22 patients, and compared non-MS-related acute transverse myelitis (ATM, n = 9), to myelitis associated with multiple sclerosis (MS-myelitis, n = 13). The ATM patients were significantly older than MS patients at the time of the myelitis diagnosis (mean age 46 vs 35, p < 0.05). ATM appeared as a "longitudinal myelitis", with fusiform cord expansion on T ₁-weighted images and intramedullary increased signal on T ₂-weighted images, each involving multiple spinal levels (mean = 7–8). However, MS-myelitis lesions appeared focal, involving significantly fewer spinal levels (mean = 1–2, p < 0.001), although the lesions were equally likely to expand the cord. Four (42%) of the ATM lesions showed abnormal, variable enhancement, whereas none of the MS myelitis lesions enhanced. Cranial MRI was more likely to be normal in ATM (78%) than in MS-myelitis patients (15%, p < 0.001). Although readily distinguishable from lesions due to MS, the various etiologies for ATM, including post-infectious ( n = 2), post-vaccination ( n = 3), and idiopathic ( n = 4) were indistinguishable on MRI. The MRI findings of an extensively lesioned, swollen cord, suspicious for an intramedullary tumor and providing a temptation for a biopsy, may reflect a non-neoplastic inflammatory disorder.