Polymorphisms of apolipoprotein E; outcome and susceptibility in multiple sclerosis

Allelic variants of the apolipoprotein E (APOE) gene influence the course of several neurological diseases. In multiple sclerosis the concentration of APOE in cerebrospinal fluid and its intrathecal synthesis is reduced. Specific isoforms of APOE may also be important and it has been suggested that possession of the epsilon4 allele may be associated with a more aggressive disease process. These data prompted us to re-examine, in a large group of patients with multiple sclerosis, the proposal that allelism in the apolipoprotein gene influences disease course. Genotypes were determined in a well-defined group of 370 unrelated Caucasians with clinically definite multiple sclerosis and in 159 healthy controls. Age at onset, sex, disease duration, disease subtype were recorded. Disability was measured using the Kurtzke expanded disability status score in patients with a disease duration of 10 years or greater. There was no significant difference in APOE allele or genotype frequencies between patients and controls, between disease subtypes or between genders. APOE genotype did not significantly influence age of onset, and no significant relationship between genotype, allele frequency and disease severity was found. This study suggests that individual APOE alleles or genotypes do not determine disease susceptibility or the clinical course of multiple sclerosis.     

The association between apolipoprotein E and multiple sclerosis

The article is a complete literature study that investigates the association between apolipoprotein E (Apo E) and multiple sclerosis (MS). Apo E is an important factor in transport, uptake, and redistribution of cholesterol, which is significant to remodelling and repair of nerve tissue. Apo E is involved in neurodegenerative diseases and the most well known association is between Apo epsilon4 and Alzheimer's disease. Only one study found that homozygosity for Apo epsilon4 does cause an increased risk of developing MS. No results indicate that heterozygosity for Apo epsilon4 causes a greater risk of developing MS. No association between the Apo epsilon4 allele and MS subgroups, age of onset, and gender has been found. The association between Apo epsilon4 and relapse rate is contradictory. Most results confirm the hypothesis about an association between the Apo epsilon4 allele and increased disease progression. Two longitudinal studies found an association between Apo epsilon4 and increased disease progression. Half of the cross-sectional studies found the same association. Four of seven published studies examining the association between Apo epsilon4 and increased disease progression using magnetic resonance imaging (MRI) found a significant association. Apo epsilon4 appears to be a predisposing factor to a faster disease progression in MS.     

Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele

BACKGROUND: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging. OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. DESIGN: A 2-year clinical and (1)H-MRS follow-up cohort study. SETTING: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. PATIENTS: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. MAIN OUTCOME MEASURE: Levels of N-acetylaspartate as measured by (1)H-MRS. RESULTS: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19). CONCLUSIONS: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.     

Anticardiolipin antibodies in Japanese patients with multiple sclerosis

We evaluated circulating anticardiolipin antibodies (aCL) in 38 Japanese patients who fulfilled the criteria of clinically definite multiple sclerosis (MS), using a newly developed EIA system with aCL-cofactor. Two of 38 patients (5.3%) had a aCL-cofactor-dependent positive serology, and differences compared with findings in controls were statistically significant. The 2 aCL-positive patients had similar clinical features with acute transverse myelopathy (ATM), optic neuropathy (OPN), normal cranial MRI and negative oligoclonal IgG bands (OCBs) in the cerebrospinal fluid (CSF). Among the 38 patients, 3 had ATM, OPN, normal cranial MRI and negative OCBs, hence, in a significant number of the patients (2/3; 67%) with these distinctive features, serology for aCL was positive. Therefore, they may have another condition associated with aCL, masquerading as MS. Serological testing for aCL with aCL-cofactor is recommended for the patients with clinical diagnosis of MS, especially for those showing OPN and ATM during the clinical course, and in Asian peoples where the incidence of ATM and OPN is relatively high among the patients with diagnosis of MS.     

Health-related quality of life in Japanese patients with multiple sclerosis

Journal of Neurology - Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related...     

Estrogen receptor gene polymorphism in Japanese patients with multiple sclerosis

Estrogen has been reported to have immunosuppressive functions, and to inhibit the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Since estrogen shows its biological effects via estrogen receptors (ER), we investigate the possible role of ER genes (ERG) in the pathogenesis of MS. PvuII and XbaI polymorphisms in ERG were detected by PCR-RFLP from the DNA of 79 conventional MS patients and 73 healthy controls. The [P] allele in the profiles in PvuII was significantly more prevalent in MS patients than in the controls (P<0.0005). In the study of XbaI polymorphism, the onset age of MS patients with the Xx genotype was earlier than that of the xx genotype group (mean age+/-S.D.; 22.60+/-8.04, and 27.49+/-9.14, respectively) (P<0.05) by ANOVA followed by Fisher's PLSD. Although the Xx genotype group tended to earlier onset age than the XX genotype group (29.60+/-11.10), this difference did not reach. On the basis of these results, PvuII polymorphism might be associated with susceptibility to MS, and XbaI polymorphism with onset age of MS. ERG polymorphism should be further studied in other populations to improve strategies for treatment of MS.     

Mitoxantrone for the treatment of Japanese patients with multiple sclerosis]

We retrospectively evaluated the benefits of mitoxantrone (MITX) treatment in Japanese patients with multiple sclerosis (MS) with more than 3 relapses per year or a deterioration of more than one Expanded Disability Status Scale (EDSS) of Kurtzke score per year despite having IFN beta 1b therapy. Monthly intravenous injections of MITX, 10-12 mg/m2, for 3 months were followed by an additional treatment every 3 months. Nine patients (6 women, 3 men) with a mean age of 39 years, a mean disease duration of 3.9 years, and a mean EDSS score of 6.7 were studied. Seven patients had long spinal cord lesions (LCL-MS). Most patients tolerated the treatment, although 2 patients stopped MITX therapy after 3 injections because of severe appetite loss. The 7 patients who continued MITX therapy for more than 3 times significantly decreased their relapse rate and EDSS deterioration. The average relapse count in the year preceding initiation of MITX therapy was 4.3 (range: 3-6)/year, EDSS score increased by 2.7 (range: 1-7)/year. The average relapse count was 2.3 (range: 0-4)/year from 0 to 6 months after MITX therapy (p = 0.114), and 1.1 (range: 0-4)/year from 7 to 12 months (p = 0.285). The average EDSS deterioration was -0.4 (range -2-1) from 0 to 6 months after MITX therapy (p = 0.018), and there was no deterioration from 7 to 12 months. Most patients received granulocyte colony stimulating factor because of leukocytopenia caused by MITX. No patients showed any decrease in cardiac ejection fraction during this observation period. For Japanese MS patients, MITX therapy was very effective to suppress relapses without incurring severe adverse events.     

Platelet-activating factor receptor gene polymorphism in Japanese patients with multiple sclerosis

We evaluated the association of the platelet-activating factor receptor (PAFR) gene polymorphism (A224D) with the susceptibility and severity of multiple sclerosis (MS) in a Japanese population. DNA was collected from 162 Japanese patients with clinically definite 'conventional' MS (MS) and 245 healthy controls. The missense mutation A224D that impairs PAF-PAFR signaling was determined by polymerase chain reaction restriction fragment length polymorphism. The frequency of the AD/DD genotypes was significantly higher in MS patients (21.0%) than in healthy controls (13.5%) (p=0.045; odds ratio (OR), 1.71; 95% confidence interval (CI), 1.01-2.89). Moreover, the frequency of D allele in MS patients (11.7%) was also significantly higher than those in healthy controls (6.9%) (p=0.019; OR, 1.78; 95% CI, 1.10-2.89). These findings suggest that the PAFR gene missense mutation has a relation to the susceptibility for MS.     

Polymorphisms in the apolipoprotein E (APOE) gene in gerontopsychiatric patients

Two recently described polymorphisms in the promoter region of the apolipoprotein E (APOE), the −491A7T and Th1/E47csT/G polymorphism, have been suggested to be associated with an increased risk for Alzheimer's disease (AD) independent from the APOE ɛ4 carrier status. We studied the association between the APOE ɛ4 polymorphism and the −491A/T and Th1E47csT/G polymorphisms in a sample of 118 healthy, non-demented controls and 239 consecutively recruited gerontopsychiatric patients diagnosed as: Alzheimer's disease (N = 89), age mild cognitive impairment (N = 32), memory complainers without any congitive deficit (N = 54) and depression/other psychiatric disorders (N = 64), to test whether the investigated polymorphisms have a high enough selectivity and specificity to distinguish between the different gerontopsychiatric disorders to differentiate AD genetically from other forms of dementia, respectively. Also a possible association with the APOE ɛ4 polymorphism was examined. We found a statistically significant association between the APOE ɛ4 allele and Alzheimer's disease (p = 0.0001) and age associated memory impairment (p = 0.006). Our study failed to show an association between the promoter polymorphisms −491A/T and Th1E47csT/G in the APOE gene and gerontopsychiatric disorders either alone or in relationship to the APOE ɛ4 polymorphism. However, if we combine our results with three previous published positive reports there seems to be an association between the −491A/T polymorphism and AD, though its size is less than found in the original publication. Accepted: 3 February 2001     

Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG

This study investigates the relation between the serological status of NMO (neuromyelitis optica)-IgG and the clinical and MRI features in Japanese patients with multiple sclerosis. Serum NMO-IgG was tested in 35 Japanese patients diagnosed with multiple sclerosis, including 19 with the optic-spinal form of multiple sclerosis (OSMS), three with the spinal form of multiple sclerosis (SMS), and 13 with the conventional form of multiple sclerosis (CMS), which affects the brain. NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (> 3 vertebral segments) spinal cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS. The two patients having CMS with NMO-IgG had unusual brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS. This newly discovered serum autoantibody was markedly associated with longitudinally extensive spinal cord lesions and with complete blindness, suggesting severe optic-spinal disease.     

C-C chemokine receptor 2 gene polymorphism in Japanese patients with multiple sclerosis

C-C chemokine receptor 2 (CCR2) is a receptor for chemoattractant protein-1 (MCP-1) and associated with infiltrating lymphocytes in chronic active multiple sclerosis (MS) lesions. To study the role of CCR2 gene in the development of MS, we investigated the CCR2-64I polymorphism in 122 MS patients and 112 healthy controls in a Japanese population. We also analysed the influence of CCR2-64I polymorphism on the clinical course, age at disease onset, and severity. The distribution of the CCR2-64I allele was significantly different between patients and controls (p=0.0187), and the 64I/64I homozygote was significantly less common in MS than in control. Logistic analysis, adjusted for HLA-DRB1*1501-positivity, revealed negative association between the CCR2-64I and MS (p=0.0204). There were no significant associations between CCR2 polymorphism and the clinical features of MS. Our results indicate that the presence of CCR2-64I allele seems to provide protection against the development of MS.     

Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis

The importance of apolipoprotein E (ApoE) and myeloperoxidase (MPO) genotypes in the clinical characteristics of multiple sclerosis (MS) has been recently emphasized. In a large group of Polish patients we have tested the hypothesis that polymorphism in ApoE and MPO genes may influence the course of the disease. Genotypes were determined in 117 MS patients (74 females and 43 males; 99 sporadic and 18 familial cases) with mean EDSS of 3.6, mean age of 44. 1 years, mean duration of the disease 12.8 years and mean onset of MS at 31.2 years, and in 100 healthy controls. The relationship between ApoE and MPO genes' polymorphism and the MS activity as well as the defect of remyelination (diffuse demyelination) and brain atrophy on MRI were analysed. The ApoE epsilon4 allele was not related to the disease course or the ApoE epsilon2 to the intensity of demyelination on MRI. The genotype MPO G/G was found in all familial MS and in 57% (56/99) of sporadic cases. This genotype was also related to more pronounced brain atrophy on MRI. The MPO G/G subpopulation was characterized by a significantly higher proportion of patients with secondary progressive MS (P < 0.05) and by a higher value of EDSS. According to our results the MPO G allele is frequently found (in 96% of cases) among Polish patients with MS. More severe nervous tissue damage in the MPO G/G form can be explained by the mechanism of accelerated oxidative stress. It seems that MPO G/G genotype may be one of the genetic factors influencing the progression rate of disability in MS patients.     

Pattern reversal visual evoked potentials in Japanese patients with multiple sclerosis.

Forty-seven Japanese patients with multiple sclerosis, 29 probable (clinically definite) and 18 possible, were studied by black-and-white checkerboard pattern reversal visual evoked potential and were compared with a control group of 20 healthy young adults. The major positive peak (P100) was found to be abnormal in 70% of all cases, 90% of probable cases and 39% of possible cases. P100 was delayed in 38% of all cases and was absent in 23% of all cases. None of the eyes showing a flat pattern response was in the acute stage of optic neuritis. The percentage of cases with no response (23% of all cases) was greater than any of the previously reported series from Western countries, substantiating the previously reported clinical features of oriental multiple sclerosis. The pattern response was absent only when testing eyes with severe visual impairment, whereas delayed latency of P100 was seen regardless of the severity of visual impairment, suggesting the usefulness of P100 latency for detecting subclinical optic nerve lesions.     

Chromosome 19 locus apolipoprotein C-II association with multiple sclerosis.

We have used a PCR based method to analyze allelic frequencies in a (TG)n(AG)m microsatellite marker located in the first intron of the apolipoprotein C-II gene in French MS patients and controls. Samples were collected from 74 MS patients and from 102 controls. The distribution of microsatellite alleles differed between patients and controls (chi 2 = 7.82), showing a significant effect (P < 0.04) with MS due to the increased frequency of the allele 6 and a decrease frequency (P < 0.03) of allele I. Our study confirms that the apolipoprotein C-II region may influence susceptibility to MS.