Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis

Background and objective

The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS) could provide mechanistic targets for therapeutic intervention.

Methods

Five magnetic resonance imaging (MRI) parameters that could potentially cause progressive disability were investigated in 43 patients with early PPMS and in 37 patients with early relapsing remitting multiple sclerosis (RRMS): atrophy in brain, both grey matter and white matter; intrinsic abnormality in brain, both grey matter and white matter (measured by the magnetisation transfer ratio (MTR)); and atrophy of the upper cervical spinal cord. Both groups were also compared with controls.

Results

Patients with PPMS were older and more likely to be men. Both patient groups had atrophy of brain grey matter and white matter, and intrinsic abnormality in MTR of normal‐appearing grey matter and white matter. Cord atrophy was present only in the PPMS (mean cord area: PPMS, 67.8 mm²; RRMS, 72.7 mm²; controls, 73.4 mm²; p = 0.007). This was confirmed by multivariate analysis of all five MRI parameters, age and sex.

Conclusion

Grey matter and white matter of the brain are abnormal in both early RRMS and PPMS, but cord atrophy is present only in PPMS. This is concordant with myelopathy being the usual clinical presentation of PPMS. Measurement of cord atrophy seems to be clinically relevant in PPMS treatment trials.About 15% of patients with multiple sclerosis present with a steadily accumulating neurological deficit—usually a spastic paraplegia that indicates spinal cord dysfunction—known as primary progressive multiple sclerosis (PPMS). These patients are older at onset (mean age 40 v 30 years) and the proportion of male patients is higher than in those with an onset of relapsing remitting multiple sclerosis (RRMS).¹ The mechanisms of disability in patients with PPMS are not well understood. Patients with PPMS become disabled at an earlier stage despite having no greater load of lesions visible on magnetic resonance imaging (MRI) of the brain,² nor have differences been noted between patients with RRMS and those with PPMS in terms of the number of focal spinal cord lesions that are visible on T2‐weighted MRI scans.^3,4 One study reported a higher frequency of diffuse hyperintensity on proton‐density‐weighted scans of the spinal cord in patients with PPMS.⁵In recent years, we have recruited two cohorts of patients in the early stages of RRMS and PPMS to investigate—using serial multimodal MRI and clinical follow‐up—potential prognostic markers and pathogenic mechanisms in the two types of multiple sclerosis. The present study directly compares quantitative MRI measures in these patients with early RRMS, those with early PPMS, and controls using identical analysis methods applied to anonymised scans by a blinded investigator (MB) to identify imaging features that might associate with the more disabling clinical course seen in PPMS. Five MRI parameters were pre‐selected for investigation because each could—if more severely abnormal—help explain disability in PPMS: (a) brain grey matter volume; (b) brain white matter volume; (c) normal‐appearing brain grey matter magnetisation transfer ratio (MTR); (d) normal‐appearing brain white matter MTR; and (e) upper cervical cord cross‐sectional area. We hypothesised that patients with early PPMS have a more disabling course of their multiple sclerosis, because one or more of the five MRI parameters is abnormal when compared with patients with early RRMS.     

Clinical characteristics of progressive relapsing multiple sclerosis

OBJECTIVE: Patients with progressive relapsing (PR) multiple sclerosis (MS) may accrue disability by incomplete recovery from acute exacerbations and by ongoing deterioration. In primary progressive (PP) MS, disability accumulates solely by continuous decline. Because it is the least common form of MS, there is scant information regarding the clinical characteristics of PRMS, but relapses are reportedly uncommon. The purpose of this study is to describe the clinical features of a cohort of patients with PRMS. METHODS: A retrospective chart review of 16 patients diagnosed with PRMS at two academic MS centres over a four-year period. RESULTS: Nine men and seven women had PRMS. The mean age at onset was 35.1+/-11.2 years. The most common presenting symptom was a progressive myelopathy. The mean disease duration was 10.1+/-8.5 years and the average time to first exacerbation was 4.1+/-3.7years. Patients had an average of 2.8+/-2.3 relapses with an annualized relapse rate of 0.6+/-0.8. Time to Expanded Disability Status Scale (EDSS) 6.0 was strongly associated with time to first exacerbation. Although there was no correlation between the number of relapses and time to EDSS 6.0, there was a modest inverse relation between time to EDSS 6.0 and annualized relapse rate. CONCLUSIONS: Relapses in PRMS may occur more often than previously described and disability may accumulate more rapidly in PRMS than in PPMS. We suggest differentiating between these two forms of MS.     

癫痫患者神经元特异性烯醇化酶和胰岛素样 生长因子1的变化及临床意义

目的观察癫痫发作3 d内患者血清神经元特异性烯醇化酶(NSE)和胰岛素样生长因子1(IGF-1)浓度的变化及其临床意义。方法选取63例特发性癫痫患者作为病例组,以37例年龄及性别相匹配的体检健康者作对照组。采用ECLIA、ELISA测定血清NSE和IGF-1的浓度。结果病例组血清NSE和IGF-1浓度与对照组比较明显升高,差异有统计学意义(P<0.05)。血清NSE和IGF-1ROC曲线下面积分别为0.767和0.663。癫痫患者血清NSE和IGF-1浓度之间存在相关性(r=0.379,P<0.01)。结论血清NSE、IGF-1浓度在痫性发作后3 d内升高,提示其可作为判断痫性发作后早期脑损伤及机体早期启动神经保护的生化指标,具一定临床应用价值。癫痫患者血清NSE和IGF-1浓度之间存在相关性,提示它们可能共同参与了癫痫的发病过程。     

Changes of insulin-like growth factor-Ⅱ and insulin-like growth factor binding protein-3 in cerebrospinal fluid of children with tuberculous meningitis

BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE: To explore the changes of insulin-like growth factor-Ⅱ (IGF-Ⅱ) and IGFBP-3 in cerebrospinal fluid (CSF) of children with tuberculous meningitis and the significance of the changes. DESIGN: A non-randomized concurrent controlled study. SETTING: Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS: Thirty children with tuberculous meningitis (14 males and 16 females) were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children (13 males and 17 females) with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children (13 males and 17 females) without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS: ① The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid (3 mL). The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ② The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS: ① Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group (P < 0.05). There was no significant difference in the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group (P > 0.05). ② Correlation: The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid (r =0.821, 0.855, P < 0.01), but negatively with the glucose (r =0.742, –0.605, P < 0.01). CONCLUSION: ① IGFs and IGFBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ② The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral encephalitis.     

Interferon beta-1b modulates serum sVCAM-1 levels in primary progressive multiple sclerosis

Endothelial activation is a key feature of multiple sclerosis (MS) pathogenesis. It is modulated by interferon beta-1b (IFNB-1b) treatment in relapsing-remitting MS (RRMS) patients. This particular pharmacodynamic effect still has to be proven in primary progressive MS (PPMS). In the current study, serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin were analyzed longitudinally in 18 PPMS patients before, during and after 12 months of treatment with IFNB-1b. During drug therapy there was a significant early and sustained increase of sVCAM-1 (overall P < 0.0001). Flu-like symptoms induced by IFNB-1b and also concomitant infections were associated with higher sVCAM-1 levels. Neutralizing antibodies to IFNB-1b were associated with lower sVCAM-1 levels. In conclusion, IFNB-1b modulates the adhesion cascade in patients with PPMS in a similar way it does in RRMS. Nevertheless, a clinical effect of IFNB in PPMS still has to be proven in a randomized controlled clinical trial.     

Serum insulin-like growth factor-I levels in amyotrophic lateral sclerosis.

The serum concentrations of the myotrophic hormone insulin-like growth factor-I (IGF-I) in 23 patients with amyotrophic lateral sclerosis were not significantly different from those found in the sera of 13 control patients. There was no difference in binding of 125I-IGF-I by serum from patients with amyotrophic lateral sclerosis in comparison with that found in the controls. These results indicate that immunoreactive IGF-I concentrations are normal in patients with amyotrophic lateral sclerosis and that such patients do not have significant antibodies binding their endogenous IGF-I.     

Cerebrospinal fluid insulin-like growth factor-1, insulin growth factor binding protein-2 or nitric oxide are not increased in MS or ALS

OBJECTIVES: Many studies have shown that nitric oxide (NO) and growth factors including insulin growth factors (IGFs) may be involved in the pathogenesis of multiple sclerosis (MS) and neurodegenerative diseases. Our previous studies suggested a relationship between cerebrospinal fluid (CSF) NO metabolites (nitrates and nitrites, NN(x)) and IGF-1 in patients with progressive encephalopathy, hypsarrhythmia and optic atrophy syndrome. MATERIAL AND METHODS: We examined CSF concentrations of NN(x), IGF-1 and IGF binding protein-2 (IGFBP-2) in 25 controls, 14 patients with MS and 14 patients with amyotrophic lateralis sclerosis (ALS). RESULTS: There were no significant differences in CSF levels of NN(x), IGF-1 or IGFBP-2 between the groups. CSF IGFBP-2 concentrations correlated significantly with age in controls, which may reflect age-related changes in the blood-brain barrier function. CONCLUSION: Upregulation of the production of NO and IGF-1 in the brain or spinal cord does not influence CSF levels of these molecules in MS or ALS.     

Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the neuromuscular system resulting in paralysis and ultimately death. Currently, no effective therapy is prescribed for patients; however, several therapeutic strategies are showing promise. Either exercise or treatment with adeno-associated virus/insulin-like growth factor-1 alone has therapeutic benefits in an amyotrophic lateral sclerosis transgenic mouse model. We show here that activity duration affects the therapeutic benefit associated with exercise, with 6- and 12-hour exposure to a running wheel providing significant motor function benefits and increased survival. Remarkably, a combination of insulin-like growth factor-1 gene delivery and exercise has profound effects on survival and function, indicative of synergistic effects with exercise and insulin-like growth factor-1. Our results indicate that a drug treatment in combination with appropriate exercise may provide the most promising therapy for amyotrophic lateral sclerosis to date.     

Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease

Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA expression array was performed to detect differential gene expression of Abeta-treated versus untreated HBP. Messenger RNA expression of leukemia inhibitory factor (LIF) and insulin-like growth factor binding protein 3 (IGFBP-3) was increased in DAbeta(1-40)-treated HBP, whereas early growth response factor-1 (Egr-1) expression was decreased. Corresponding protein expression was investigated in AD and control brains. In all AD cases examined, LIF expression was observed in senile plaques and cerebral amyloid angiopathy, whereas IGFBP-3 expression in these lesions was only observed in a subset of cases. LIF and IGFBP-3 were also expressed in neurofibrillary tangles, as well as in neurons in AD and control brains. Egr-1 was predominantly expressed in astrocytes. Given its known involvement in both neuronal and immune responses to injury, the cytokine LIF may be a mediator of the inflammatory reaction seen in AD. IGFBP-3 is known to inhibit cell proliferation and induce apoptosis and may therefore contribute to neuronal degeneration in AD.     

Interferon beta-1a in primary progressive multiple sclerosis

There is currently no disease-modifying treatment proven to be of efficacy in primary progressive multiple sclerosis (PPMS). However, a number of therapeutic trials have recently been specifically designed for this group. These include a randomised controlled trial of interferon beta-1a which is discussed here. It is hoped that therapeutics in primary progressive multiple sclerosis will continue to expand and effective therapeutic agents will be developed.     

Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis.

OBJECTIVE: To 1) compare monthly serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-type 1 (TIMP-1) in patients with relapsing-remitting MS (RRMS) versus healthy controls and 2) determine the relationship among monthly serum levels of MMP-9 and TIMP-1 and MRI activity. BACKGROUND: Activated T-cells and macrophages secrete MMPs that may facilitate their migration across vascular subendothelial basement membranes into the CNS. The serum concentration of MMP-9 is reported to be higher in patients with RRMS than healthy controls. METHODS: Monthly evaluations including gadolinium-enhanced (Gd+) brain MRI and measures of serum MMP-9 and TIMP-1 were performed for up to 15 months in 24 patients with RRMS and for up to 4 months in 10 controls. RESULTS: Serum MMP-9 but not TIMP-1 levels are elevated in RRMS patients compared to healthy controls (p = 0.025, p = 0.61). In a univariate analysis, high MMP-9 and low TIMP-1 levels precede appearance of new Gd+ lesions (respectively; odds ratio = 3.3, p = 0.008; odds ratio = 2.2, p = 0.086). In a multivariate analysis, in comparison to months when MMP-9 is low and TIMP-1 high, MRI scans obtained the month following high MMP-9 and low TIMP-1 serum concentrations are more likely to report new Gd+ lesions (p = 0.0006, odds ratio = 21.5). CONCLUSION: An increase in the activity of matrix metalloproteinase-9 (MMP-9) relative to tissue inhibitor of MMP-type 1 (TIMP-1) may be related to formation of new MS lesions, suggesting that serum levels of MMP-9 and TIMP-1 may be surrogate markers of disease activity in relapsing-remitting MS.     

Cognitive impairment in relapsing and primary progressive multiple sclerosis: mostly a matter of speed.

Based on the assumption that cognitive impairment in MS is consistent with subcortical dementia, a battery of neuropsychological tests was assembled that included measures of executive function (Tower of London and Wisconsin Card Sorting Test), verbal learning and memory (a paired associates learning test), and speeded information processing (Stroop Color Word Interference Test). The battery was administered to patients with relapsing and primary progressive MS and to healthy controls. Differences between patients and controls occurred on several of the measures. However, when differences with respect to fatigue and depression were statistically controlled, the only differences that remained significant involved measures relating to the speed of information processing. Patients performed more slowly than controls, with the disparity being greater for relapsing patients than for those with primary progressive disease. The slowing was evident on measures of automatic as well as controlled processing and regardless of whether speed was an explicit feature of successful performance or recorded unobstrusively while the patient concentrated on planning a correct solution to a problem. Parallels were noted between cognitive slowing associated with MS and that of normal aging.     

Insulin-like growth factor-1 and insulin-like growth factor binding proteins in cerebrospinal fluid during the development of mouse embryos

Insulin-like growth factor-1 (IGF-1) is a potent neurotrophic factor that promotes the proliferation, migration and differentiation of glial and neuronal cells. IGF-1 can also protect neurons from undergoing apoptotic cell death. IGF-1 is produced by the choroid plexus, located in the ventricles. Knowledge of embryonic CSF composition at different developmental stages could be the key to understanding the behavior of neuroepithelial cells (neural stem and progenitor cells). In this study, CSF was aspirated from the lateral ventricle of embryonic mice using micromanipulation and the total concentration of IGF-1 and IGF binding proteins (IGFBPs) was measured on gestational days 12 to 21 (E12–E21). Analysis using Western blot and enzyme-linked immunosorbent assay showed that IGF-1 levels in the CSF decreased from days E12 to E15, increased rapidly from days E16 to E18 and decreased from days E19 to E21. Days E16 to E18 coincide with the onset of neuron proliferation, and migration and organization of the cytoarchitecture of the developing cortex. The concentration of IGFBPs in CSF samples from E12 to E21 did not change. Since CSF is in contact with the cerebral cortical germinal epithelium, changes in CSF IGF-1 concentration could affect the activity of the germinal epithelium and be involved in cerebral cortical development.     

Serum sAPO-1/Fas levels in multiple sclerosis

Soluble APO-1 (sAPO-1) may prevent apoptosis of lymphocytes induced by activation of the APO-1/Fas receptor. Objectives – To determine sAPO-1 levels in the serum of multiple sclerosis (MS) patients and controls in order to investigate if abnormal lymphocyte apoptosis occurs in this disease. Methods – Serum samples from patients with MS, other neurological diseases, systemic lupus erythematosus and healthy controls were determined by enzyme-linked immunosorbent assay. Results – We did not detect differences in mean serum sAPO-1 levels between patients with multiple sclerosis and controls. Conclusions – This preliminary study suggests that resistance of peripheral blood lymphocytes to apoptosis mediated by sAPO-1 is not likely to be a major factor in the development of autoreactive cells in MS.     

Immunologic factors in primary progressive multiple sclerosis

Primary progressive multiple sclerosis (PPMS) is clinically characterized by progression without remission or relapse, in contrast to relapsing forms of MS. Pathologic and imaging findings also indicate that PPMS differs from relapsing forms. Recent studies examining potential immunologic differences among MS forms suggest that cytokine and adhesion molecule expression profiles, but not chemokine receptor profiles, in PPMS patients resemble those in healthy controls more than those in patients with relapsing MS. However, the significance of these findings remains to be fully elucidated, and there is little additional evidence as yet of marked differences among MS forms based on immunologic characteristics. Of interest are the recent demonstrations that activated immune cells produce brain-derived neurotrophic factor (BDNF), a neuroprotective factor, in MS lesions, that BDNF receptors are located in MS tissue, and that glatiramer acetate (GA)-specific T cells produce BDNF irrespective of T helper cell Th1 or Th2 phenotype. These findings both support the concept of a protective inflammation in MS and suggest an additional mechanism of action for the clinical effects of GA therapy in MS. Whether and to what extent this mechanism is present in different MS forms remain to be clarified.     

胰岛素样生长因子结合蛋白3增强子元件(IEE)的生物学特征**☆◆

背景：在细胞水平，胰岛素样生长因子结合蛋白3竞争性地与胰岛素样生长因子结合阻止了胰岛素样生长因子与其受体结合，从而抑制了胰岛素样生长因子的活性。 目的：观察衰老细胞中调节性蛋白质胰岛素样生长因子结合蛋白3的生物学特征。 设计、时间及地点：单一样本观察，于2006-09/2007-09在西安交通大学生物医学信息工程教育部重点实验室完成。 材料：人胚肺二倍体成纤维细胞(2BS)购于中国生物制品研究所。 方法：用Northern的方法显示胰岛素样生长因子结合蛋白3基因的表达在年轻和衰老的2BS细胞中存在差异；聚合酶链反应扩增出人类胰岛素样生长因子结合蛋白3上游包括5’-UTR区的2kb的序列，并用酶切得到4组不同长短的胰岛素样生长因子结合蛋白3启动子片段并确定可调控转录活性的区域；通过重叠寡核苷酸凝胶阻滞实验确定在该活性区域中的增强子元件-IEE(IGFBP-3 enhancer element)及其与蛋白结合的碱基序列等；用DNase I Footprinting法确定了IEE中与蛋白结合的核心序列。 主要观察指标：①胰岛素样生长因子结合蛋白3基因在年轻和衰老细胞中的表达差异。②通过重叠寡核苷酸确定增强子元件。③通过凝胶阻滞试验证实该复合物结合活性与衰老相关的。④通过凝胶阻滞试验确定IEE与蛋白结合的碱基序列。⑤用DNase I Footprinting法确定IEE中与蛋白结合的核心序列。⑥判断与IEE结合蛋白的相对分子质量。 结果：与年轻的2BS细胞相比，衰老的2BS细胞中胰岛素样生长因子结合蛋白3基因的表达升高； 5’-cca gcc tgc caa gca gcg tgc ccc ggt tgc-3’是胰岛素样生长因子结合蛋白3的增强子元件；该元件与蛋白结合的核心序列是CTG CCA和GCG TGC CCC G，而且这种结合是与衰老相关的；结合蛋白的相对分子质量大约在27 000。 结论：在2BS细胞中发现了一个新的转录增强子，它与蛋白结合的核心序列是CTG CCA和GCG TGC CCC G，可与一个大约27 000的蛋白结合；在衰老细胞中可选择性地促进胰岛素样生长因子结合蛋白3的表达。