Multiple Sclerosis Mortality Rates in Canada, 1975-2009.

BACKGROUND: This study examined mortality due to multiple sclerosis (MS) in Canada, 1975-2009 to determine whether there has been a change in age at death relative to the general population and decrease in MS mortality rates. METHODS: Mortality rates/100,000 population for MS and all causes were calculated using data derived from Statistics Canada, age-standardized to the 2006 population. RESULTS: The average annual Canadian MS mortality rate, 1975-2009 was 1.23/100,000. Five-year rates for 1975-79, 1980-84, 1985-89, 1990-94, 1995-99, 2000-04, 2005-09 were: 1.16, 0.94, 1.01, 1.16, 1.30, 1.43, 1.33. Trend analysis showed mortality rates over the entire 35 years were stable (average annual percent change of less than one percent). The average annual 1975-2009 rates for females and males were 1.45 and 0.99. Five-year female rates were always higher than males. Regardless of gender, there was a decrease in MS mortality rates in the 0-39 age group and increases in the 60-69, 70-79, and 80+ groups over time. In contrast, there were decreases in all-cause mortality rates across each age group. The highest MS mortality rates for 1975-2009 were consistently in the 50-59 and 60-69 groups for both genders, while the highest all-cause mortality rates were in the 80+ group. CONCLUSIONS: Changes in the age distribution of MS mortality rates indicate a shift to later age at death, possibly due to improved health care. However MS patients remain disadvantaged relative to the general population and changes in age at death are not reflected in decreased mortality rates.

Cerebrospinal Fluid in a Small Cohort of Patients with Multiple Sclerosis Was Generally Free of Microbial DNA.

Multiple sclerosis (MS) is a common cause of non-traumatic neurologic disability with high incidence in many developed countries. Although the etiology of the disease remains elusive, it is thought to entail genetic and environmental causes, and microbial pathogens have also been envisioned as contributors to the phenotype. We conducted a metagenomic survey in cerebrospinal fluid (CSF) from 28 MS patients and 15 patients suffering other type of neurological conditions. We detected bacterial reads in eight out of the 15 non-MS patients and in a single MS patient, at an abundance >1% of total classified reads. Two patients were of special interest: one non-MS patient harbored ~73% bacterial reads, while an MS patient had ~83% bacterial reads. In the former case, Veillonella parvula, a bacterium occasionally found associated with meningitis was the predominant species, whilst Kocuria flava, apparently an environmental bacterium, predominated in the latter case. Thirty-four out of 43 samples contained <1% bacterial reads, which we regard as cross- or environmental contamination. A few viral reads corresponding to Epstein-Barr virus, cytomegalovirus, and parvovirus were also identified. Our results suggest that CSF of MS patients is often (but not always) free of microbial DNA.

Decision-making under explicit risk is impaired in multiple sclerosis: relationships with ventricular width and disease disability.

BACKGROUND: Decision-making is an essential function of everyday life. Decision-making under explicit risk requires developing advantageous decision strategies based on fixed outcomes (e.g., probabilities of winning or losing a bet). Decision-making and its neural substrates have been rarely studied in MS. We expected performance in decision-making under risk to be lowered in MS patients, and negatively correlated with disease-related disability, cognition, and ventricular width. METHODS: Three groups were included: 32 MS patients and 20 healthy controls were examined with conventional neuropsychological tests and the Game-of-Dice Task (GDT) assessing decision-making under explicit risk. Linear 2-D ventricular width was assessed on MS patients' clinical MRIs and compared to a third group, 20 non-MS neurological control patients. RESULTS: Compared to healthy controls, MS patients showed impaired GDT and neuropsychological performance, depending on the MS-subtype (relapsing-remitting (RR), n = 22; secondary progressive, n = 10) and disability severity among RR-MS patients. In MS patients, GDT performance correlated with processing speed, intercaudate ratio, and third ventricle ratio (p's < 0.05). Mediation analysis showed that the link between GDT performance and processing speed was fully explained by ventricular size. CONCLUSION: Decision-making under explicit risk was reduced in MS patients, but only those with more pronounced disability. Independent of processing speed, decision-making under explicit risk correlates inversely with central atrophy in MS.

Validation of quantitative susceptibility mapping with Perls' iron staining for subcortical gray matter.

Quantitative susceptibility mapping (QSM) measures bulk susceptibilities in the brain, which can arise from many sources. In iron-rich subcortical gray matter (GM), non-heme iron is a dominant susceptibility source. We evaluated the use of QSM for iron mapping in subcortical GM by direct comparison to tissue iron staining. We performed in situ or in vivo QSM at 4.7 T combined with Perls' ferric iron staining on the corresponding extracted subcortical GM regions. This histochemical process enabled examination of ferric iron in complete slices that could be related to susceptibility measurements. Correlation analyses were performed on an individual-by-individual basis and high linear correlations between susceptibility and Perls' iron stain were found for the three multiple sclerosis (MS) subjects studied (R(2) = 0.75, 0.62, 0.86). In addition, high linear correlations between susceptibility and transverse relaxation rate (R2*) were found (R(2) = 0.88, 0.88, 0.87) which matched in vivo healthy subjects (R(2) = 0.87). This work validates the accuracy of QSM for brain iron mapping and also confirms ferric iron as the dominant susceptibility source in subcortical GM, by demonstrating high linear correlation of QSM to Perls' ferric iron staining.

Traumatic injury and multiple sclerosis: a systematic review and meta-analysis.

A systematic review/meta-analysis of literature addressing a possible association between traumatic injury and onset of multiple sclerosis was conducted. Medline, Embase, Cochrane DSR, Ovid HealthStar, CINAHL, ISI Web of Science and Scopus were searched for analytical studies from 1950 to 2011. Two investigators independently reviewed articles for inclusion, assessing their quality using the Newcastle-Ottawa Scale. Of the 13 case-control studies included, 8 were moderate quality and 5 low; of the 3 cohort studies 2 were high and 1 moderate. Meta-analysis including moderate and low quality case-control studies produced a modest but significant odds ratio: 1.41 (95% confidence interval: 1.03, 1.93). However, when low quality studies were excluded, the resulting odds ratio was non-significant. Cohort studies produced a non-significant standardized incidence ratio of 1.00 (95% confidence interval: 0.86, 1.16). These findings support the conclusion that there is no association between traumatic injury and multiple sclerosis onset; more high quality cohort studies would help to confirm this observation.

Multiple sclerosis: validation of MR imaging for quantification and detection of iron.

PURPOSE: To investigate the relationship between iron staining and magnetic resonance (MR) imaging measurements in postmortem subjects with multiple sclerosis (MS). MATERIALS AND METHODS: Institutional ethical approval was obtained, and informed consent was obtained from the subjects and/or their families. Four MR imaging methods based on transverse relaxation (T2 weighting, R2 mapping, and R2* mapping) and phase imaging were performed by using a 4.7-T system in three in situ postmortem patients with MS less than 28 hours after death and in one in vivo patient 1 year before death. Iron staining with the Perls iron reaction was performed after brain extraction. Region-of-interest measurements from six subcortical gray matter structures were obtained from MR imaging and then correlated with corresponding locations on photographs of iron-stained pathologic slices by using a separate linear least-squares regression in each subject. Iron status of white matter lesions, as determined by staining, was compared with appearance on MR images. RESULTS: R2* mapping had the highest intrasubject correlations with iron in subcortical gray matter (R(2) = 0.857, 0.628, and 0.685; all P < .001), while R2 mapping (R(2) = 0.807, 0.615, 0.628, and 0.489; P < .001 and P = .001, .034, and .001, respectively), phase imaging (R(2) = 0.672, 0.441, 0.596, 0.548; all P ≤ .001), and T2-weighted imaging (R(2) = 0.463, 0.582, 0.650, and 0.551; all P < .001) had lower but still strong correlations. Within lesions, hypointense areas on phase images did not always represent iron. A hyperintense rim surrounding lesions on R2* maps was only present with iron staining, yet not all iron-staining lesions had R2* rim hyperintensity. CONCLUSION: All four MR imaging methods had significant linear correlations with iron and could potentially be used to determine iron status of subcortical gray matter structures in MS, with R2* mapping being preferred. A reliable method of determining iron status within MS lesions was not established.

Change in the Health-Related Quality of Life of Multiple Sclerosis Patients over 5 Years.

This study examined whether multiple sclerosis (MS) patients (N = 3779) experience change in their perceived health-related quality of life (HRQOL) over a 5-year period, and investigated baseline factors that may be related to change in HRQOL. Data from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry were used to address the study's research questions. Results for the physical and mental component scores of the 12-item Short Form Health Status Survey, version 2 (SF-12v2), indicated that most of the MS sample experienced no significant changes over a 5-year period. However, 40% and 36% of the sample experienced clinically significant declines in their physical and mental HRQOL, respectively, over the 5-year period. After controlling for baseline scores, having a lower education, having greater duration since disease diagnosis, not being employed, having a lower income, not receiving a disease-modifying therapy, and taking a greater number of prescription medications were significantly associated with a clinically significant decline in physical HRQOL. After controlling for baseline scores, not being married/partnered, experiencing a greater number of relapses, not being employed, having a lower income, and taking a greater number of prescription medications were significantly associated with a clinically significant decline in mental HRQOL. Overall, most of the MS sample remained stable in their HRQOL over time. However, approximately four out of every ten patients experienced a clinically important decline in their HRQOL. While the association was statistically significant, the sociodemographic and disease-related factors linked with decline did not strongly predict decline over a 5-year period.

Impaired neurosteroid synthesis in multiple sclerosis.

High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription-polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis.

Detecting lesions in multiple sclerosis at 4.7 tesla using phase susceptibility-weighting and T2-weighting.

PURPOSE: To demonstrate 4.7 Tesla (T) imaging methods for visualizing lesions in multiple sclerosis in the human brain using phase susceptibility-weighting and T2 weighting. MATERIALS AND METHODS: Seven patients with relapsing-remitting multiple sclerosis were imaged at 4.7T using three-dimensional (3D) susceptibility-weighted imaging (SWI) with 0.90 mm(3) voxel volumes, and with 2D T2-weighted fast spin echo (T2WFSE) with 0.34 mm(3) voxels and 1.84 mm(3) voxels. The visibility of MS lesions at 4.7T with phase SWI and T2WFSE was assessed by independent lesion counts made by an experienced neuroradiologist, and by quantitative measures. RESULTS: High resolution T2WFSE at 4.7T provided excellent depiction of hyperintense lesions. When combined with phase SWI, 124 total lesions were identified of which 18% were only visible on phase SWI and not on T2WFSE. The phase lesions had a mean phase shift relative to local background of -11.15 +/- 5.97 parts per billion. CONCLUSION: Imaging at 4.7T can provide both high quality, high resolution T2WFSE and SWI for visualization of lesions in multiple sclerosis. Phase susceptibility-weighting can identify additional lesions that are not visible with high resolution T2WFSE.

Early life exposure to lipopolysaccharide suppresses experimental autoimmune encephalomyelitis by promoting tolerogenic dendritic cells and regulatory T cells.

The rising incidence of autoimmune diseases such as multiple sclerosis (MS) in developed countries might be due to a more hygienic environment, particularly during early life. To investigate this concept, we developed a model of neonatal exposure to a common pathogen-associated molecular pattern, LPS, and determined its impact on experimental autoimmune encephalomyelitis (EAE). Mice exposed to LPS at 2 wk of age showed a delayed onset and diminished severity of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, induced at 12 wk, compared with vehicle-exposed animals. Spinal cord transcript levels of CD3epsilon and F4/80 were lower in LPS- compared with PBS-exposed EAE animals with increased IL-10 levels in the LPS-exposed group. Splenic CD11c(+) cells from LPS-exposed animals exhibited reduced MHC class II and CD83 expression but increased levels of CD80 and CD86 both before and during EAE. MOG-treated APC from LPS-exposed animals stimulated less T lymphocyte proliferation but increased expansion of CD4(+)FoxP3(+) T cells compared with APC from PBS-exposed animals. Neuropathological studies disclosed reduced myelin and axonal loss in spinal cords from LPS-exposed compared with PBS-exposed animals with EAE, and this neuroprotective effect was associated with an increased number of CD3(+)FoxP3(+) immunoreactive cells. Analyses of human brain tissue revealed that FoxP3 expression was detected in lymphocytes, albeit reduced in MS compared with non-MS patients' brains. These findings support the concept of early-life microbial exposure influencing the generation of neuroprotective regulatory T cells and may provide insights into new immunotherapeutic strategies for MS.

The burden of multiple sclerosis: a community health survey.

BACKGROUND: Health-related quality of life (HRQL) in persons with multiple sclerosis (MS) who reside within the community relative to the general population is largely unknown. Data from the Canadian Community Health Survey Cycle 1.1 (CCHS 1.1) were used to compare HRQL of persons with MS and the general population. METHODS: A representative sample of adults (18 years or older) from the cross sectional population health survey, CCHS 1.1, was examined to compare scores on the Health Utilities Index Mark 3 (HUI3), a generic preference-based HRQL measure, of respondents with (n = 302) and without (n = 109,741) MS. Selected sociodemographic covariates were adjusted for in ANCOVA models. Normalized sampling weights and bootstrap variance estimates were used in the analysis. RESULTS: The mean difference in overall HUI3 scores between respondents with and without MS was 0.25 (95% CI: 0.20, 0.31); eight times greater than the clinically important difference. The largest differences in scores were seen with the ambulation (0.26; 95% CI: 0.20, 0.32) and pain attributes (0.14; 95% CI: 0.09, 0.19). Clinically important differences with dexterity and cognition were also observed. CONCLUSION: While the proportion of the Canadian population with MS is relatively small in comparison to other diseases, the magnitude of the burden is severe relative to the general population.

Comparative expression of human endogenous retrovirus-W genes in multiple sclerosis.

Human endogenous retroviruses (HERVs) have been associated with multiple sclerosis (MS) pathogenesis. Several related HERV-W sequences have been implicated in disease occurrence and progression; the MS retrovirus (MSRV) is one such element whose envelope protein has been recently demonstrated to be involved in innate immune pathogenesis. To distinguish MSRV from other HERV-W sequences we analyzed the relative abundance of individual HERV-W env sequences by employing a real-time PCR approach using specific oligonucleotide primers and tissue samples from MS and non-MS patients. Our analyses reveal that ERVWE1 env-encoding DNA and RNA exhibited increased detection (p < 0.05) and expression (p < 0.01) in the brains of MS patients. Similarly, ERVWE1 env transcripts were inducible in glial cells (p < 0.05), while comparable changes in MSRV abundance were not observed. These results indicate that individual HERVs might have distinct roles in MS pathogenesis.

The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: a role for endoplasmic reticulum chaperones in astrocytes.

Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05). Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05). Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05). Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.

Prevalence of multiple sclerosis in First Nations people of Alberta.

BACKGROUND: Multiple Sclerosis (MS) is reported to be uncommon among North American aboriginals despite frequent intermarriage with people of European ancestry, but few population-based studies have been conducted. The purpose of this study was to determine the prevalence of MS among First Nations aboriginal people in Alberta, Canada compared to the general population. METHODS: All hospital in-patient and physician fee-for-service records between 1994 and 2002 where a diagnosis of MS was mentioned were extracted from government health databases in the province of Alberta. First Nations people can be identified since the federal government (Health Canada) pays health care insurance premiums on their behalf. Multiple Sclerosis prevalence per 100,000 population for both First Nations people and the general population of Alberta were calculated for each year during this time span. RESULTS: Among First Nations in Alberta, MS prevalence was 56.3 per 100,000 in 1994 and 99.9 per 100,000 in 2002, an increase of 43.6%. In 2002 prevalence was 158.1 and 38.0 for females and males respectively, a female to male ratio of 4.2:1. Multiple Sclerosis prevalence among the general population of Alberta was 262.6 per 100,000 in 1994 and 335.0 per 100,000 in 2002, an increase of 21.6%. In 2002 prevalence was 481.5 and 187.5 for females and males respectively, a female to male ratio of 2.6:1. Peak prevalence for both First Nations and general population females in 2002 was age 50-59, also 50-59 for both First Nations and general population males. CONCLUSION: While MS prevalence in First Nations people is lower than in the general population of Alberta, it is not rare by worldwide standards.

Incidence of multiple sclerosis among First Nations people in Alberta, Canada.

Multiple sclerosis (MS) is thought to be rare among North American aboriginals, although few population-based frequency studies have been conducted. Data from government health databases were used to describe the incidence of MS among First Nations aboriginal people in the province of Alberta compared to the general population from 1994 to 2002. The general population rates were consistently higher than First Nations rates, but were essentially stable across this time span for both groups. For First Nations the MS incidence was 7.6 per 100,000 and 20.6 per 100,000 for the general population in 2002. During 2000-2002 for First Nations the incidence was 12.7 for females and 7.6 for males, with a female-to-male ratio of 1.7:1. During the same period the general population incidence was 32.2 for females and 12.7 for males, with a female-to-male ratio of 2.5:1. The peak incidence for both First Nations and the general population of Alberta was in the age group 30-39 years in 2002. The high incidence rates are consistent with high prevalence rates reported for both groups in 2002: 99.9 per 100,000 for First Nations and 335.0 per 100,000 for the general population. While the MS incidence in First Nations people is lower than in the general population of Alberta, it is not rare by worldwide standards.

A comparison of written materials vs. materials and counselling for women with sexual dysfunction and multiple sclerosis.

AIM: Evaluate whether symptoms of vaginal dryness, low libido, less intense or delayed orgasm could be improved in women with multiple sclerosis who took part in an education or education plus counselling programme. BACKGROUND: Sexual dysfunction, a prevalent symptom in women with multiple sclerosis, can negatively affect quality-of-life. METHODS: Women attending a large multiple sclerosis clinic were invited and 62 were randomized into one of two groups. Group 1 received written materials on primary, secondary and tertiary sexual dysfunction in multiple sclerosis as well as additional resources (books, websites, list of local psychologists specializing in sexual counselling). Group 2 received the same written materials as well as three counselling sessions from the clinic nurse, the latter two by telephone. The primary outcome measures were the expanded disability status scale and the multiple sclerosis intimacy and sexuality questionnaire-19. Repeated-measures analysis of variance was used to evaluate sexual dysfunction score over time and to compare two groups. RESULTS: At baseline, total expanded disability status scale scores were not correlated with primary, secondary or tertiary sexual dysfunction. Total multiple sclerosis intimacy and sexuality questionnaire-19 score was correlated with use of anti-cholinergic medications [r (54) = 0.28, P < 0.05], but no other medications, alcohol or tobacco use. Both groups had equivalent and significant reductions in primary sexual dysfunction [F (1) = 14.79, P < 0.001] postintervention. There was a trend towards an interaction effect for tertiary sexual dysfunction [F (1) = 2.88, P = 0.096], in the direction of group 2 (education and counselling). Subjectively, women welcomed the opportunity to discuss sexual concerns and noted that the written information allowed a framework for initiating discussion with their spouses. CONCLUSION: Relatively straightforward interventions provided by a clinic nurse may help women cope with the symptoms of sexual dysfunction associated with multiple sclerosis. Women who do not benefit from basic interventions could then be referred to an expert sexual dysfunction practitioner. RELEVANCE TO CLINICAL PRACTICE: Women with multiple sclerosis experience many disease-related physical and emotional challenges of which sexuality is only one. Sensitivity to sexual dysfunction and being willing to approach the topic is appreciated by women with multiple sclerosis. Nurses do not require in-depth expertise to offer some basic suggestions which may significantly improve life quality and assist the woman with multiple sclerosis to talk about or cope with sexuality issues.

Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis.

The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties of inflammation and neurodegeneration. We investigated the role of PAR2 in the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. PAR2 expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05). Macrophages and astrocytes from PAR2 wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR2 KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001). PAR2 activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01). Myelin oligodendrocyte glycoprotein-induced EAE caused more severe inflammatory gene expression in the CNS of PAR2 WT animals (P < 0.05), together with enhanced T cell proliferation and interferon gamma production (P < 0.05), compared with KO littermates. Indeed, PAR2 WT animals showed markedly greater microglial activation and T lymphocyte infiltration accompanied by worsened demyelination and axonal injury in the CNS compared with their PAR2 KO littermates. Enhanced neuropathological changes were associated with a more severe progressive relapsing disease phenotype (P < 0.001) in WT animals. These findings reveal previously unreported pathogenic interactions between CNS PAR2 expression and neuroinflammation with ensuing demyelination and axonal injury.

Lipid microarrays identify key mediators of autoimmune brain inflammation.

Recent studies suggest that increased T-cell and autoantibody reactivity to lipids may be present in the autoimmune demyelinating disease multiple sclerosis. To perform large-scale multiplex analysis of antibody responses to lipids in multiple sclerosis, we developed microarrays composed of lipids present in the myelin sheath, including ganglioside, sulfatide, cerebroside, sphingomyelin and total brain lipid fractions. Lipid-array analysis showed lipid-specific antibodies against sulfatide, sphingomyelin and oxidized lipids in cerebrospinal fluid (CSF) derived from individuals with multiple sclerosis. Sulfatide-specific antibodies were also detected in SJL/J mice with acute experimental autoimmune encephalomyelitis (EAE). Immunization of mice with sulfatide plus myelin peptide resulted in a more severe disease course of EAE, and administration of sulfatide-specific antibody exacerbated EAE. Thus, autoimmune responses to sulfatide and other lipids are present in individuals with multiple sclerosis and in EAE, and may contribute to the pathogenesis of autoimmune demyelination.