Experimental acute dorsal compression of cat spinal cord: correlation of magnetic resonance signal intensity with spinal cord evoked potentials and morphology.

The aim of this study was to determine whether solitary pulmonary tuberculoma and malignant tumor can be differentiated on the basis of magnetic resonance (MR) signal intensity. Twenty-eight patients with solitary pulmonary lesions were prospectively studied with MR imaging: T1-weighted, enhanced T1-weighted, proton density-weighted, and T2-weighted spin echo images were obtained. The confirmation methods used were computed tomography (CT)-guided biopsy in seven patients with lung cancer and four patients with tuberculosis; surgery in ten patients with lung cancer and five patients with tuberculosis; and laboratory data in two patients with tuberculosis. Morphologic features and MR signal intensity were examined in detail. As the test for detection of tuberculoma, signal difference on T2-weighted images was carefully analyzed. The signal intensity ratio of the nodule to thoracic muscle signal intensity was measured. The signal intensities obtained from the lung cancers and tuberculomas were variable on pre-and post-enhanced T1-weighted images and proton density-weighted images. Masses were hypointense in 2 of 17 patients with lung cancer and in 9 of 11 patients with tuberculoma on T2-weighted images (sensitivity 82%, specificity 89%, accuracy 87%). The mean signal intensity ratios of the tuberculomas to muscle were significantly lower than those of malignant tumors on T1-weighted, enhanced T1-weighted, proton density-weighted, and T2-weighted images (P < 0.0001). After gadolinium-DTPA enhancement, 2 malignant tumors and 7 tuberculomas showed a marginal rim enhancement pattern, whereas 15 malignant tumors and 2 tuberculomas revealed a diffuse enhancement. The results of MR imaging were consistent with those of CT in 84% of the patients. MR imaging is a helpful adjunctive method in terms of differentiating a tuberculoma from a malignant tumor.

An evidence-based analysis of published radiologic criteria for assessing spinal canal compromise and cord compression in patients with acute cervical spinal cord injury. This study was conducted to determine whether literature-based guidelines could be established for accurate and objective assessment of spinal canal compromise and spinal cord compression after cervical spinal cord injury. Before conducting multicenter trials to determine the efficacy of surgical decompression in cervical spinal cord injury, reliable and objective radiographic criteria to define and quantify spinal cord compression must be established. A computer-based search of the published English, German, and French language literature from 1966 through 1997 was performed using MEDLINE (U.S. National Library of Medicine database) to identify studies in which cervical spinal canal and cord size were radiographically assessed in a quantitative manner. Thirty-seven references were included for critical analysis. Most studies dealt with degenerative disease, spondylosis, and stenosis; only 13 included patients with acute cervical spinal cord injury. Standard lateral radiographs were the most frequent imaging method used (23 studies). T1- and T2-weighted magnetic resonance imaging were used to assess spinal cord compression in only 7 and 4 studies, respectively. Spinal cord size or compression were not precisely measured in any of the cervical trauma studies. Interobserver or intraobserver reliability of the radiologic measurements was assessed in only 7 (19%) of the 37 studies. To date, there are few quantitative, reliable radiologic outcome measures for assessing spinal canal compromise or cord compression in patients with acute cervical spinal cord injury.

A multicenter, retrospective study using computed tomographic and magnetic resonance imaging data to establish quantitative, reliable criteria of canal compromise and cord compression in patients with cervical spinal cord injury. To develop and validate a radiologic assessment tool of spinal canal compromise and cord compression in cervical spinal cord injury for use in clinical trials. There are few quantitative, reliable criteria for radiologic measurement of cervical spinal canal compromise or cord compression after acute spinal cord injury. The study included 71 patients (55 men, 16 women; mean age, 39.7 +/- 18.7 years) with acute cervical spinal cord injury. Causes of spinal cord injury included motor vehicle accidents (n = 36), falls (n = 20), water-related injuries (n = 8), sports (n = 5), assault (n = 1), and farm accidents (n = 1). Canal compromise was measured on computed tomographic scan and T1- and T2-weighted magnetic resonance imaging, and cord compression at the level of maximum injury was measured on T1- and T2-weighted magnetic resonance imaging. All films were assessed by two independent observers. There was a strong correlation of canal compromise and/or cord compression measurements between axial and midsagittal computed tomography, and between axial and midsagittal T2-weighted magnetic resonance imaging. Spinal canal compromise assessed by computed tomography showed a significant although moderate correlation with spinal cord compression assessed by T1- and T2-weighted magnetic resonance imaging. Virtually all patients with canal compromise of 25% or more on computed tomographic scan had evidence of some degree of cord compression on magnetic resonance imaging, but a large number of patients with less than 25% canal compromise on computed tomographic scan also had evidence on magnetic resonance imaging of cord compression. In patients with cervical spinal cord injury, the midsagittal T1- and T2-weighted magnetic resonance imaging provides an objective, quantifiable, and reliable assessment of spinal cord compression that cannot be adequately assessed by computed tomography alone.

Magnetic resonance imaging (MRI) on patients with temporomandibular joint disorders (TMD) has revealed that a decrease and/or increase in signal intensity from retrodiscal tissue, joint effusion (the excessive accumulation of joint fluid) and articular disc displacement are related to TMD. However, the effect of aging on these phenomena has yet to be clarified. This study was carried out to explore the relationship between changes in signal intensity from retrodiscal tissue, joint fluid status and pathological disc conditions in elderly patients with TMD. Twenty patients aged over 60 years were examined. They consisted of one man and 19 women, and ranged between 60 and 79 years in age (mean, 66.0 years). The relationships between decreased signal intensity on proton-density-weighted (PDW) images and increased signal intensity on T2-weighted (T2W) MR images from retrodiscal tissue, joint fluid status and state of articular disc were examined. Joint fluid status was classified into 5 levels by extent of high signal areas in upper and lower articular spaces on T2W images. Disc displacement status was evaluated by PDW images. The Wilcoxon test was applied for the statistical analysis. The group showing increased T2W signal intensities from the retrodiscal tissue consisted of 31 out of 40 joints (77.5%). This group showed a significant difference in comparison with the other groups in which no apparent joint fluid was shown (p<0.05). There were no statistically significant differences among other categories. The results suggest a negative relationship between joint fluid and increased signal intensity from retrodiscal tissue due to reflection of the inflammatory reaction in TM joints.

Objective To investigate whether increased signal intensity (ISI) can help assess the prognosis in patients with cervical spondylotic myelopathy (CSM) by means of measuring the ratio of signal intensity. Methods A retrospective study with two or more years follow-up of 57 patients with CSM underwent posterior cervical decompression were carried out from February 2000 to February 2006. 1.5T MRI was performed in all patients before surgery. T2-weighted images (T2WI) of sagittal ISI on the cervical spinal cord were obtained, For those with ISI, the values of signal intensity of the spinal cord on T2-weighted image (T2Wl) and TI-weighted image (TIWI) of sagittal view were measured at the location where there was ISI on T2WI, and the ratio of signal intensity of T2WI / T1WI (T2/T1 ratio) at the same level of the spinal cord and with similar area was calculated on the computer. Patients with ISI were subdivided into 2 groups according to T2/T1 ratio. Results ISI was not observed in 20 patients (group 1). The range of T2/T1 ratio of other 37 patients was from 1.28 to 2.80 and the median was 1.65. Nineteen patients were divided into group 2 (ratio range, 1.28-1.63), and 18 into group 3 (ratio range, 1.67-2.80). Significant differences were noted in age at surgery, duration of disease, recovery rate, pre and preoperative JOA score among three different groups.Spearman's rank correlation showed that T2/T1 ratio was positively correlated with age at surgery and duration of disease, negatively with pre- and postoperative JOA score and recovery rate. Conclusion Patients with ISI and higher T2/T1 ratio tend to have relatively severe preoperative state of illness and poor prognosis after surgical intervention. Spinal cord signal intensity change on T2-weighted MRI might be a predictor of a poor outcome in terms of functional recovery rate in patients underwent operations for multi-level CSM. Key words: Cervical vertebrae; Spinal cord compression; Magnetic resonance imaging

The goal of this study was to determine the long-term clinical significance of and the risk factors for intramedullary signal intensity change on MR images in patients with cervical compression myelopathy (CCM), an entity most commonly seen with cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament (OPLL). One hundred seventy-four patients with CCM but without cervical disc herniation, severe OPLL (in which the cervical canal is < 10 mm due to OPLL), or severe kyphotic deformity (> 15 degrees of cervical kyphosis) who underwent surgery were initially selected. One hundred eight of these patients were followed for > 36 months, and the 71 patients who agreed to MR imaging examinations both pre- and postsurgery were enrolled in the study (the mean follow-up duration was 60.6 months). All patients underwent cervical laminoplasty. The authors used the Japanese Orthopaedic Association (JOA) score and recovery ratio for evaluation of pre- and postoperative outcomes. The multifactorial effects of variables such as age, sex, a history of smoking, diabetes mellitus, duration of symptoms, postoperative expansion of the high signal intensity area of the spinal cord on MR imaging, sagittal arrangement of the cervical spine, presence of ventral spinal cord compression, and presence of an unstable cervical spine were studied. Change in intramedullary signal intensity was observed in 50 of the 71 patients preoperatively. The pre- and postoperative JOA scores and the recovery ratio were significantly lower in the patients with signal intensity change. The mean JOA score of the upper extremities was also significantly lower in these patients. Twenty-one patients showed hypointensity in their T1-weighted images, and a nonsignificant correlation was observed between intensity in the T1-weighted image and the mean JOA score and recovery ratio. The risk factors for signal intensity change were instability of the cervical spine (OR 8.255, p = 0.037) and ventral spinal cord compression (OR 5.502, p < 0.01). Among these patients, 16 had postoperative expansion of the high signal intensity area of the spinal cord. The mean JOA score and the recovery ratio at the final follow-up were significantly lower in these patients. The risk factor for postoperative expansion of the high signal intensity area was instability of the cervical spine (OR 5.509, p = 0.022). No significant correlation was observed between signal intensity on T1-weighted MR images and postoperative expansion of the intramedullary high signal intensity area on T2-weighted MR images. Long-term clinical outcome was significantly worse in patients with intramedullary signal intensity changes on MR images. The risk factors were instability of the cervical spine and severe ventral spinal compression. The long-term clinical outcome was also significantly worse in patients with postoperative expansion of the high signal intensity area. The fact that cervical instability was a risk factor for the postoperative expansion of the high signal intensity indicates that this high signal intensity area occurred, not only from necrosis secondary to ischemia of the anterior spinal artery, but also from the repeated minor traumas inflicted on the spinal cord from an unstable cervical spine. The long-term neurological outcome found in the preliminary study of patients with CCM who had cervical instability and intramedullary signal intensity changes on MR images suggests that surgical treatment should include posterior fixation along with cervical laminoplasty or anterior spinal fusion.

This study retrospectively reviewed magnetic resonance imaging and delayed computed tomography after myelography of cervical spondylotic myelopathy patients who needed surgical treatment. The purpose of this study is to clarify the meaning of high magnetic resonance intensity areas in cervical spondylotic myelopathy patients. There is no conclusion whether the high magnetic resonance signal intensity areas can be a predictor for surgical results or not. Thirty-one patients with cervical spondylotic myelopathy were examined with magnetic resonance imaging before surgery and delayed computed tomography after surgery. The presence or absence of high intensity areas in the spinal cord was compared with clinical symptoms and surgical outcomes. Twenty-three (74%) of 31 patients showed high intensity areas in the spinal cord on the T2-weighted image. Among these 23 patients, 18 revealed bilateral intramedullary "snake eyes" enhancement in delayed computed tomography. The presence of high intensity areas did not correlate with the surgical outcomes. Patients with multisegmental (linear) high intensity areas frequently manifested muscle atrophy in upper extremities. High intensity areas on T2-weighted magnetic resonance imaging were not correlated with the severity of myelopathy or surgical outcomes evaluated by the Japanese Orthopaedic Association score. Magnetic resonance imaging or delayed computed tomography in this study could not rule out the presence of white matter changes, including axonal loss or demyelination. Multisegmental (linear) high intensity areas on T2-weighted magnetic resonance imaging were associated with clinical evidence of extensive anterior horn cell and radiographic evidence of gray matter cavitation.

Subacute compression of the spinal cord was applied to rats. The animals were chronologically observed using magnetic resonance imaging for more than 8 weeks after surgery and were killed for histopathologic examination. To investigate the correlation of changes in signal intensity on magnetic resonance images with those observed in histopathologic study and with the degree of spinal cord compression and paralysis. No consensus has been reached concerning the correlation of magnetic resonance images to clinical symptoms of compressive myelopathy. Few reports are available in which magnetic resonance imaging findings are compared with histopathologic features in chronic or subacute experiments. In rats under general anesthesia, the T11 lamina was thinned and a slow increase in volume was applied. Hind limb paralysis appeared 1 week after the procedure and spontaneously subsided thereafter. The degree of spinal compression and signal intensity was observed chronologically using magnetic resonance imaging. The signal intensity on the final MR images was rated on a four-point scale and compared with histopathologic findings. As spinal compression increased, the incidence of high signal intensity on long spin-echo images became higher. Low signal intensities on short spin-echo images were visible in animals in which compression and paralysis were the most severe. In these animals, cavitation and a dilated central canal were visible. High signal intensities on long spin-echo images reflected various pathologic changes. Changes in signal intensity on MR images are visible after the induction of myelopathy by high-pressure compression. These signal intensities may be useful in predicting the outcome of compressive myelopathy.

Multiple myeloma presenting with acute bony spinal cord compression and mechanical instability successfully managed nonoperatively

12. Angiotensin-II type-1 receptor blockade decreased T2 signal intensity in spinal cord compression in symptomatic cervical spondylotic myelopathy

Objective To evaluate the magnetic resonance (MR) signal intensity changes in the sacrococcygeal region of patients with uterine fibroids treated with high intensity focused ultrasound (HIFU). Materials and Methods Two hundred and sixty-seven patients with uterine fibroids treated with HIFU between January and December 2016 were retrospectively reviewed. All patients underwent enhanced pre- and post-HIFU MRI. Multivariate analysis was used to assess the relationship between the factors and the signal intensity changes in the sacrum and the soft tissue adjacent to the sacrum. Results Among the 267 patients, 122 (46%) had MR signal intensity changes in the sacrum and/or the soft tissue adjacent to the sacrum after HIFU. Multivariate analysis showed that the position of the uterus, the distance from the dorsal side of the fibroid to the sacrum, and the ablation efficiency were significantly correlated with MR signal intensity changes in the sacrum and the soft tissue adjacent to the sacrum. Further analysis showed a significant relationship between the location of the MR signal intensity changes and uterine size, the enhancement degree of the uterus. Leg pain was only seen in patients with MR signal intensity changes both in the sacrum and the soft tissue adjacent to the sacrum. Conclusions The location of the uterus, the distance between the dorsal side of the fibroids to the sacrum, and ablation efficiency have a significant relationship with the MR signal intensity changes. The size of the uterus and the degree of enhancement are related to the locations of MR signal changes.

Background:Acute low back pain is a common cause for presentation to the emergency department (ED). Since benign etiologies account for 95% of cases, red flags are used to identify sinister causes that require prompt management.Objectives:We assessed the effectiveness of red flag signs used in the ED to identify spinal cord and cauda equine compression.Patients and Methods:It was a retrospective cohort study of 206 patients with acute back pain admitted from the ED. The presence or absence of the red flag symptoms was assessed against evidence of spinal cord or cauda equina compression on magnetic resonance imaging (MRI).Results:Overall, 32 (15.5%) patients had compression on MRI. Profound lower limb neurologic examination did not demonstrate a statistically significant association with this finding. The likelihood ratio (LR) for bowel and bladder dysfunction (sensitivity of 0.65 and specificity of 0.73) was 2.45. Saddle sensory disturbance (sensitivity of 0.27 and specificity of 0.87) had a LR of 2.11. When both symptoms were taken together (sensitivity of 0.27 and specificity of 0.92), they gave a LR of 3.46.Conclusions:The predictive value of the two statistically significant red flags only marginally raises the clinical suspicion of spinal cord or cauda equina compression. Effective risk stratification of patients presenting to the ED with acute back pain is crucial; however, this study did not support the use of these red flags in their current form.

Objective To investigate the relationship between the cervical MR images and pathological changes, prognosis in patients with cervical spinal stenosis and cervical spondylotic myelopathy. Methods From Nov. 2006 to Nov. 2009, 286 patients with cervical spondylotic myelopathy were included through retrospective analysis. All patients were divided into two groups according to whether there was cervical stenosis, the grade of increased signal intensity (ISI) in spinal cord and the degree of spinal cord compression was evaluate in T2-weighted MR images of midian sagittal slices. JOA scale, duration of disease,Hoffmann sign, Babinski sign, sensory loss or hypoesthesia, and lower-extremity/upper-extremity hyperreflexia were recorded. Results The incidence rate of cervical spinal stenosis was 33.6% in patients with cervical spondylotic myelopathy. The study showed that the age was smaller (P＜ 0.001 ), preoperative JOA score was higher(P=0.0018), duration of disease was longer(P=0.009), and the recovery rate was lower(P＜ 0.001 )in cervical spinal canal narrowing group comparing with control group. There was no significant difference between the two groups in gender (x2=0.006,P=l.00). There was significant difference between two groups in the incidence of ISI in spinal cord through x2 test(x2=62.396,P＜ 0.001 ). Multivariate analysis indicated that the likelihood of the recovery rate of cervical myelopathy decreased with the presence of cervical spinal stenosis, duration of dieaase, number of neurological signs, age (R2=0.565). Conclusion Patients with congenitally narrow cervical spinal canal have to suffer severe spinal cord compression and high incidence of ISI in spinal cord. The duration of disease is long, and prognosis is poor. Key words: Cervical vertebrae; Spinal stenosis; Spinal cord compression; Magnetic resonance imaging

Full text Figures and data Side by side Abstract Editor's evaluation Introduction Results Discussion Methods Data availability References Decision letter Author response Article and author information Metrics Abstract Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents. Editor's evaluation This important study combined MRI(magnetic resonance imaging) imaging and histopathology to examine the remyelination of brain lesions in an EAE marmoset model of multiple sclerosis. This work addresses in a non-human primate a missing link in the neuropathology of myelin repair, because in human MS it is virtually impossible to study the lesion dynamics by MRI (in live patients) and demyelination by histology (upon brain autopsy). The data presented are solid although the conclusions would have been stronger with further histological evidence of remyelination. https://doi.org/10.7554/eLife.73786.sa0 Decision letter Reviews on Sciety eLife's review process Introduction Multiple sclerosis (MS) is a debilitating inflammatory demyelinating disorder affecting millions worldwide (Reich et al., 2018). MS causes dynamic changes to myelin in the central nervous system, including the quintessential focal inflammatory destruction of myelin, as well as the phenomenon of remyelination that can follow the demyelination (Lubetzki et al., 2020; Brown et al., 2014; Chari, 2007; Lassmann et al., 1997). Demyelinated axons are susceptible to persistent damage and neurological dysfunction in MS; therefore, remyelination is a crucial aspect of tissue repair, and as such represents an important therapeutic target (Kremer et al., 2019). Most knowledge about remyelination in MS derives from postmortem studies using histochemistry and electron microscopy. This is because investigating remyelination in vivo in real time is limited by imperfect discrimination on neuroimaging modalities such as magnetic resonance imaging (MRI). Furthermore, in human beings, where collecting serial short-interval scans is challenging, it is difficult to detect and track the dynamic occurrence of remyelination. Therefore, to investigate the pathobiology of remyelination in the context of focal inflammatory demyelination, a reliable preclinical model is needed to develop techniques that can then be applied clinically. Rodent models have been widely used to investigate various aspects of the pathobiology of demyelination. However, while toxin models in mice, including the lysolecithin and cuprizone models, display demyelination and even remyelination, they do not recapitulate the recruitment of peripherally derived adaptive immune cells that occurs in MS, which can potentially confound the MRI signal (Kipp et al., 2012; Kipp et al., 2017). Conversely, rodent experimental autoimmune encephalomyelitis (EAE) models, though driven by an immune response, are often neither focally nor profoundly demyelinating and mostly impair the spinal cord. There is no known rodent model that is characterized by multifocal inflammatory demyelination in the brain that resembles MS and is disseminated in both space and time. However, EAE in the common marmoset (Callithrix jacchus) is a well-recognized translational model that serves as a bridge between the rodent EAE and human MS (Jagessar et al., 2016; Kap et al., 2010; Kap et al., 2016). Not only does EAE resemble MS white matter lesions (WML) both radiologically and pathologically (Sati et al., 2012; Maggi et al., 2017), but marmoset WML spontaneously remyelinate (Lee et al., 2019), as occurs in MS. Prior studies demonstrated that certain signal changes in MRI, such as magnetization transfer ratio (MTR), correlate with demyelination and remyelination in MS lesions (Chen et al., 2008; Chen et al., 2013; Filippi et al., 2012; Absinta et al., 2016; Laule and Moore, 2018). This has also been investigated in animal models, albeit mainly in rodent cortex (Yano et al., 2018; Schmierer et al., 2010) rather than white matter. It has also been demonstrated that partial remyelination can occur and can be localized either to specific parts of the lesion (most commonly the lesion edge) or to the whole lesion (Filippi et al., 2019; Patrikios et al., 2006). Here, we studied focal WML in marmoset EAE. We utilized serial in vivo MRI, mainly involving proton density-weighted (PDw), T1-weighted (T1w) before and after intravenous injection of a gadolinium chelate, and MTR sequences, to age and characterize lesions and predict remyelination. We further analyzed WML histopathology, focusing on myelin lipids and proteins as well as mature oligodendrocytes and their precursors, to compare and study the reliability of using various in vivo MRI sequences to predict remyelination in the context of recovery from inflammatory demyelination. Results Lesion characterization and categorization on MRI EAE was induced in six marmosets as described, and the animals followed by MRI at regular intervals until sacrifice due to clinical progression. Lesions were grouped into three categories. Those categorized as ‘early active’ at histopathology typically remained hyperintense on PDw images until the terminal scan and grew rapidly to several cubic millimeters, subsequently showing minimal lesion volume change over time (example in Figure 1A–B) and were enhancing on terminal T1w MRI with gadolinium contrast. Lesions classified as ‘chronic, at least partially demyelinated,’ demonstrated areas of PDw hyperintensity that persisted until the terminal scan despite resolution of early gadolinium enhancement on T1w images (Figure 2A–B). Lesions classified as ‘remyelinated’ were initially hyperintense on PDw images, with subsequent return toward isointensity over time (Figure 3A–B). None of the lesions returning to isointensity on PDw images demonstrated gadolinium enhancement on T1w images at terminal MRI. Figure 1 Download asset Open asset Example of an early active demyelinating EAE lesion with persistent hyperintensity on PDw MRI and active inflammatory demyelination on histopathology. (A) In vivo PDw MRI acquired before EAE induction (baseline) and at various timepoints leading up to the terminal scan. Images were processed as described in Methods. Red arrows: focal white matter lesion first detected 16 weeks after immunization, which persisted through the terminal MRI 3 weeks later. Red boxes: location of magnified insets. (B) Temporal evolution of volume (blue line) and normalized PDw signal intensity (orange line) of the segmented lesion. (C) Histochemical panel magnification of the same lesion, demonstrating inflammation (Iba1+microglia/macrophage infiltration) and demyelination (loss of normal PLP staining). (D) Higher magnification images from the center of the lesion (red boxes in C) showing increased cellularity, loss of myelin lipid (LFB), partial loss of oligodendrocytes and their precursors (ASPA/Olig2), partial loss of axons (Biel), and edema (increased intercellular spaces). Scale bars = 200 µm. Hematoxylin counterstaining used for PLP and Iba1. Lesion selected from M#6. Abbreviations: EAE, experimental autoimmune encephalomyelitis; PDw, proton density-weighted; MRI, magnetic resonance imaging; PLP, proteolipid protein; LFB-PAS, Luxol fast blue–periodic acid Schiff; Biel, Bielschowsky; ASPA, aspartoacylase. Figure 2 Download asset Open asset Example of a chronic, at least partially demyelinated EAE lesion core with long-lasting hyperintensity on serial PDw MRI and complete loss of myelin on histopathology. (A) In vivo PDw MRI acquired before EAE induction (baseline) and at various timepoints leading up to the terminal scan. Images were processed as described in Methods. Red arrows: focal white matter lesion first detected 23 weeks after immunization, which persisted through the terminal MRI 32 weeks later. Red boxes: location of magnified insets. (B) Temporal evolution of volume (blue line) and normalized PDw signal intensity (orange line) of the segmented lesion. (C) Histochemical panel magnification of the same lesion, demonstrating mild inflammation (Iba1+ microglia/macrophage infiltration) as well as demyelination (loss of normal PLP staining). (D) Higher magnification images from the center of the lesion (red boxes in C) showing minimally increased cellularity, partial loss of myelin lipid (LFB), loss of oligodendrocytes and their precursors (ASPA/Olig2), and loss of axons (Biel). Scale bars = 200 µm. Hematoxylin counterstaining used for PLP and Iba1. Lesion selected from M#3. Abbreviations: EAE, experimental autoimmune encephalomyelitis; PDw, proton density-weighted; MRI, magnetic resonance imaging; PLP, proteolipid protein; LFB-PAS, Luxol fast blue–periodic acid Schiff; Biel, Bielschowsky; ASPA, aspartoacylase. Figure 3 Download asset Open asset Example of a nearly complete remyelinated EAE lesion with initial hyperintensity that returned to isointensity on serial PDw MRI. (A) In vivo PDw MRI acquired before EAE induction (baseline) and at various timepoints leading up to the terminal scan. Images were processed as described in Methods. Red arrows: focal white matter lesion first detected 27 weeks after immunization, which largely resolved on MRI and could not be reliably segmented on the terminal MRI 32 weeks later. Red boxes: location of magnified insets. (B) Temporal evolution of volume (blue line) and normalized PDw signal intensity (orange line) of the segmented lesion. (C) Histochemical panel magnification of the same lesion, demonstrating pale myelin lipid staining (LFB) and near-normal levels of myelin protein (PLP). (D) Higher magnification images from the center of the lesion (red boxes in C) showing minimal inflammation (Iba1), presence of oligodendrocytes and their precursors (ASPA/Olig2), and partial preservation of axons (Biel). Scale bars = 200 µm. Hematoxylin counterstaining used for PLP and Iba1. Lesion selected from M#3. Abbreviations: EAE, experimental autoimmune encephalomyelitis; PDw, proton density-weighted; MRI, magnetic resonance imaging; PLP, proteolipid protein; LFB-PAS, Luxol fast blue–periodic acid Schiff; Biel, Bielschowsky; ASPA, aspartoacylase. In vivo PDw MRI is sensitive to lesion remyelination Using in vivo MRI only, 40 focal WML were detected in the 6 EAE marmosets (Table 1). Interrater reliability for PDw MRI classification was 94%, with Cohen’s kappa of 0.89, and consensus was achieved across the raters for all lesions. Of the 40 lesions, 12 (30%) were classified as predicted early active, 10 (25%) as predicted chronic at least partially demyelinated, and 18 (45%) as predicted remyelinated. Four of the six animals demonstrated predicted remyelinated lesions (M#1–4), whereas the remaining two only had predicted acute demyelinating and chronic, at least partially demyelinated lesions (M#5–6). Table 1 Classification of focal lesions by proton density-weighted magnetic resonance imaging. AnimalPredicted early activePredicted chronic, at least partially demyelinatedPredicted remyelinatedTotalM#11269M#21168M#31146M#40123M#53306M#66208Total12101840 Based on the histological classification criteria, 31 lesions were identified in the 5 animals with postmortem tissue (M#1 was not included in the histological analysis). Twelve of the 31 lesions (39%) were classified as early active, 10 (32%) as chronic at least partially demyelinated, and 9 (29%) as remyelinated (Table 2). All three animals with predicted remyelinated lesions on MRI (M#2–4) had remyelinated lesions on histology. M#5 and M#6 only harbored early active and chronic, at least partially demyelinated lesions, consistent with MRI findings. Two lesions in M#2 and one in M#4 were identified as predicted remyelinated on MRI but chronic, at least partially demyelinated on histology. Table 2 Classification of focal lesions by histopathology. AnimalEarly activeChronic, at least partially demyelinatedRemyelinatedTotalM#21348M#31146M#40213M#53306M#67108Total1210931 Of the 31 focal WML identified on both in vivo PDw MRI and histology, classification was concordant for 27 WML (87%). When lesions were grouped by myelination status only (i.e. early active or chronic, at least partially demyelinated vs. remyelinated), in vivo PDw MRI predicted 19 demyelinated lesions and 12 remyelinated lesions, whereas histology showed 22 demyelinated and 9 remyelinated lesions (Table 3). Relative to histology, PDw MRI prediction was therefore 100% sensitive and 90% specific for remyelination. Table 3 Confusion matrix for PDw MRI prediction of demyelinated vs. remyelinated lesions compared to histology. n=31Predicted demyelination by MRIPredicted remyelination by MRIActual demyelination by histology19322Actual remyelination by histology0991912 MTR is less sensitive to lesion remyelination than PDw MTR was also used to classify lesions using a similar rater-based analysis to that applied to the PDw images. The sensitivity and specificity for predicting remyelination, relative to histology, were 82% and 79%, respectively. T1w gadolinium enhancement as a marker of acute inflammation Across the six animals scanned longitudinally, 82% of the lesions newly detected on PDw MRI presented T1w gadolinium enhancement. Enhancement was occasionally seen at the following timepoint (10–15 days after first detection). No chronic, at least partially demyelinated or remyelinated WML presented gadolinium enhancement on the terminal scan. M#5–6 presented at least one early active WML enhancing lesion at their terminal scan. Lesion remyelination occurs over a 4- to 9-week period and is sensitive to lesion size Based on longitudinal MRI imaging of EAE lesions and analysis of normalized PDw signal intensity, with comparison to histology, we found that inflammation and demyelination were dominant in lesions younger than 10 weeks of age, corroborating previous work (Lee et al., 2019; Lee et al., 2018). In four representative lesions that remyelinated, PDw signal intensity stabilized near baseline between 4 and 9 weeks after initial lesion detection on MRI (Figure 4). Lesions larger than 0.5 µL at peak, as measured on PDw MRI, did not return to isointensity and correspondingly remained at least partially demyelinated on histology. On the other hand, most lesions smaller than 0.5 µL returned to isointensity and appeared remyelinated on histology. Figure 4 Download asset Open asset Evolution of in vivo PDw MRI signal intensity of remyelinating EAE lesions shows a typical 4- to 9-week time course of remyelination. Vertical axis: mean PDw signal intensity relative to gray matter. Horizontal axis: weeks post-immunization. Blue line corresponds to mean normalized PDw signal intensity (with standard deviation) of the segmented lesion, relative to gray matter signal intensity, quantified in a region of interest drawn manually and located in the normal appearing white matter area before the lesion appeared and kept constant over time. Normal white matter displays an average normalized signal intensity of 0.65–0.75. Vertical red arrows indicate EAE immunization. Vertical red bars indicate days when corticosteroid treatments were administered (M#1 was treated twice). Horizontal red double arrows indicate the estimated period of demyelination. Horizontal green double arrows indicate the estimated period of remyelination based on the downward slope of intensity measurement, followed by plateauing of signal intensity drop. Green titles indicate that the lesion subtype was confirmed with histopathology. M# corresponds to animal number in Table 4. Abbreviations: PDw, proton density-weighted; EAE, experimental autoimmune encephalomyelitis; MRI, magnetic resonance imaging; M, marmoset; wks, weeks. Table 4 Demographics and experimental information for the six marmosets included in this study. Immunizations used human white matter homogenate. Experiment duration corresponds to the time between immunization and terminal MRI. AnimalSexAge (years)First immunizationSecond immunizationCorticosteroid treatmentExperiment duration (weeks)M#1*Male3.7100 mg200 mgYes40M#2*Male3.7100 mg200 mgNo54M#3†Male6.2200 mg–Yes61M#4†Male6.2200 mg–No60M#5‡Female2.8200 mg–Yes18M#6‡Female2.8200 mg–No16 Denote the three different pairs of twin animals. Remyelination is independent of corticosteroid administration Per protocol, three of the six marmosets were given corticosteroids for 5 consecutive days to determine whether this treatment might alter lesion fate (principally remyelination). However, we found no differences in the prevalence of predicted remyelinated lesions based on corticosteroid treatment status. On serial PDw MRI, 10 of 21 lesions (48%) were predicted to be remyelinated in corticosteroid-treated marmosets, compared to 8 of 19 (42%) in untreated animals. Based on histological analysis in animals with available tissue, 4 of 12 lesions (33%) in corticosteroid-treated marmosets were remyelinated, compared to 5 of 19 (27%) lesions in untreated marmosets. The point biserial correlation model analysis showed that steroid administration had no significant correlation with remyelination detected on MRI (p=0.8). The average experimental duration also did not differ (40 weeks in treated and 43 weeks in untreated marmosets; p=0.85). Histological analyses also did not reveal differences between treated and untreated lesions. Histological quantification recapitulates MRI rater analysis of lesion myelin status Assessment of proteolipid protein (PLP) staining in 31 lesions and 10 normal appearing white matter (NAWM) areas (1500 µm2 centered over the lesion core) demonstrated larger unstained areas in early active (58 ± 25%) and chronic, at least partially demyelinated (38 ± 25%) lesions compared to remyelinated lesions (4.5 ± 1.1%) or NAWM (2.6 ± 0.3%) (Figure 5A). LFB assessment showed similar results: 63 ± 26% unstained area in early active lesions, 43 ± 26% in chronic, at least partially demyelinated lesions, 15 ± 25% in remyelinated lesions, and 3.0 ± 0.4% in NAWM (Figure 5B). We observed a significantly smaller unstained PLP area in NAWM compared to remyelinated lesions (two-sample t-test, p<0.001). There were no apparent differences between PLP and LFB staining in the different lesion categories and in NAWM (two-sample t-test). Interestingly, one lesion appeared remyelinated on PLP, with less than 6% of unstained area, but demyelinated on LFB (82% of unstained area). Figure 5 Download asset Open asset Histological quantification of myelin highlights different patterns across lesion categories and NAWM. Cells were quantified in a region of interest of 1500 µm2 centered on each lesion core. Percentage of demyelination quantified for each lesion category and NAWM on PLP (A) and LFB (B). Number of ASPA and Olig2 double-positive oligodendrocytes (C) and ASPA negative, Olig2-positive OPC (D) in different lesion categories and NAWM. Data in A and B highlight more demyelination in acute and chronic lesions compared to remyelinated lesions or NAWM. Data in C and D highlight more mature oligodendrocytes in remyelinated lesions and NAWM compared to acute and chronic lesions, as well as more OPC in acute lesions compared to chronic lesions, remyelinated lesions, or NAWM. (E) Bubble plot of the 31 lesions and NAWM investigated with histopathology. Vertical axis: counts of ASPA- Olig2+ OPC. Horizontal axis: counts of ASPA+ Olig2+ oligodendrocytes. Bubble color: red; acute lesions, yellow; chronic lesions, green; remyelinated lesions, purple; NAWM. Bubble size: volume on PDw at the terminal scan in mm3. ANOVA: *p<0.05, **p<0.005. Abbreviations: NAWM, normal appearing white matter; PLP, proteolipid protein; LFB, Luxol fast blue; ASPA; aspartoacylase; ANOVA, analysis of variance; OPC, oligodendrocyte progenitor cells; PDw, proton density-weighted. Oligodendrocyte and OPC counts are consistent with degree of demyelination in lesions Quantitative assessment of ASPA+/Olig2+ (mature oligodendrocytes) and ASPA-/Olig2+ (oligodendrocyte precursor cell [OPC]) across the 31 lesions and 10 NAWM areas showed, as expected, more mature oligodendrocytes in remyelinated lesions and NAWM than early active or chronic, at least partially demyelinated lesions (Figure 5C). Consistent with PLP observations, we observed significantly more oligodendrocytes in NAWM compared to remyelinated lesions (two-sample t-test, p<0.001). Interestingly, more OPC were found in early active demyelinating lesions than in remyelinated lesions or NAWM (Figure 5D). Younger lesions (<10 weeks of age by MRI) had more OPC than older lesions, highlighted by a negative correlation between lesion age and OPC count (r=–0.46; p=0.009). Discussion In this study, we determined whether high-resolution, serial, in vivo conventional PDw MRI can effectively predict remyelination status in focal WML of marmoset EAE, a relatively faithful MS model. We found that remyelination is relatively common in this model: four of the six marmosets studied had remyelinated lesions on either MRI or histopathology, and nearly half (18) of the 40 lesions identified on MRI were predicted to be remyelinated. In people, WML repair is an age-dependent process that is variable across patients and clinical disease classification (Chari, 2007; Lassmann et al., 1997; Patrikios et al., 2006). Interestingly, the two animals that did not show remyelination by in vivo MRI, M#5 and M#6, had the shortest experimental duration (16–18 weeks, compared to 40–61 weeks for the other four animals), suggesting more aggressive lesions and/or insufficient time for remyelination. Our characterization of remyelinated lesions showed low residual levels of inflammation (microglia/macrophages) and an extensive but incomplete (using NAWM as reference) repopulation of mature oligodendrocytes, specifically a higher number of ASPA+/Olig2+ cells in the lesion core compared to chronic, at least partially demyelinated lesions. Lower of unstained area on LFB and PLP consistent with data from MS (Chari, 2007; et al., et al., et al., was also observed in remyelinated lesions. lesions were nearly to white matter at the terminal in vivo PDw MRI timepoint and showed no enhancement on T1w images. Interestingly, one lesion appeared remyelinated on PLP with less than 6% of unstained area but demyelinated on LFB (82% of unstained and hyperintense on PDw MRI. This potentially for of myelin lipids vs. protein in the context of remyelination (Chari, described, MRI to be more sensitive to of myelin lipid than of myelin protein et al., 2017). expected, assessment of early active and chronic, at least partially demyelinated lesions showed mature oligodendrocytes in the lesion core and as well as a of demyelinated area on LFB and PLP early active and chronic, at least partially demyelinated were hyperintense on terminal in vivo PDw MRI. data that in marmoset EAE, lesions that initially as hyperintense on PDw MRI and subsequently return toward isointensity over time are remyelination. Our data further that signal intensity time as well as lesion can be used to lesion status in the of early lesion and despite the that PDw MRI is also known to be sensitive to other than The time course of marmoset EAE lesion and repair is relatively as confirmed work from has that lesions the period of demyelination 6 weeks (Lee et al., 2019), consistent with data from this study Figure 4). The time course of marmoset remyelination is than demyelinating models in further of the marmoset EAE model for preclinical testing of remyelination in MS et al., 2019). Our data also the of a lesion, size the lesion most not the repair process and Of the 12 early active lesions, 7 showed an increased number of ASPA-/Olig2+ cells in the lesion (Figure This observed in remyelinated lesions or NAWM, a OPC response, which indicate repair or potentially an inflammatory of OPC in this et al., In this study, we compared PDw and MTR MRI, MTR is widely used to remyelination in vivo in MS (Chen et al., 2008; Chen et al., 2013; et al., and found that in the context of marmoset EAE, PDw, in with histopathology, to have higher sensitivity and specificity for remyelination status. MTR be low in remyelinated lesions compared to white matter because of the presence of incomplete or myelin et al., 2014; et al., which from due to as a of signal intensity PDw signal intensity is measured by the MRI system, and PDw more reliable for the presence or of remyelination and for time determine whether corticosteroid treatment the course of lesion repair, half of the marmosets each twin the one that showed lesions treatment We found no differences by corticosteroid treatment status in prevalence or time course of remyelination on either MRI or histological However, it that of corticosteroid treatment might remyelination. it is that early of corticosteroid treatment as the first lesion was in this study, in treatment before lesions were even 1 This might have been early to lesion as the initial demyelination period typically weeks before remyelination It is also that of inflammation corticosteroid treatment could have more remyelination by of myelin which is a for OPC recruitment et al., and et al., 2019; et al., 2016). The of the study is This is partially by on lesions, rather than the number of animals. is that different EAE immunization were applied across marmosets, though we did not in lesion evolution or either radiologically or previous studies from with a similar of EAE induction have also not consistent differences in disease course or lesion pathobiology (Lee et al., 2019; Lee et al., 2018). we did not to myelin as we were in a of on tissue, and as lesions were found at a of relative to which would such In in vivo longitudinal PDw MRI can effectively predict remyelination in the context of marmoset EAE, with high sensitivity and specificity relative to histology. between marmoset EAE and MS with to lesion and repair, a for preclinical and clinical studies to investigate remyelinating Methods EAE induction marmosets pairs of four and two at same used for two different were included in the study (Table 4). a study, two marmosets first of human white matter followed by an 200 after no lesions were detected by in vivo MRI 2 after the initial injection (Lee et al., 2019; Lee et al., 2018). to the of early disease four marmosets 200 of white matter at All white matter were with complete

目的 评价MRI在地方性氟骨症脊柱病变诊断中的作用.方法对81例地方性氟骨症的脊柱MRI进行分析和与X线比较.结果所有椎体内脂肪含量减少和分布不均,在T1WI上信号强度表现为均匀或不均匀性减低,其信号减低程度与X线骨密度的增高程度相比较无明确相关性.32例C3～7椎体的T1WI信号强度平均值明显低于100例对照组(P<0.001).81例中后纵韧带和黄韧带骨化71例(88%),其中后纵韧带骨化35例(43%),黄韧带骨化8例(10%),后纵韧带和黄韧带骨化28例(35%),与X平片所显示的相同.在T1WI上63例后纵韧带骨化和36例黄韧带骨化有中等信号强度区者分别为32例(51%)和31例(86%).81例中椎间盘突出68例(84%),椎间盘变性57例(70%),椎管狭窄75例(92%),脊髓受压63例(78%),其中脊髓内有病理学改变28例(35%).X线测量57例颈椎椎管前后径<9 mm(以此推断脊髓受压)41例(71.92%),MRI显示脊髓受压48例(84.21%,P=0.115).57例颈椎椎间盘后突出51例(89.47%),明显高于对照组(62%)(P<0.001);椎间盘变性37例(64.91%),与对照组(37%)相比较差异有非常显著性意义(P=0.001).结论 MRI显示地方性氟骨症的椎体信号强度均匀或不均匀性减低,可反应成骨活动增强程度和氟化钙及骨髓内脂肪含量及分布.MRI对显示脊髓受压,脊髓内病理学改变和椎间盘突出、变性优于X线。