Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic ...standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis.
A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated.
Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR = 1.79, 95% CI: 1.12-2.87, p = 0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR = 0.56, 95% CI: 0.40-0.78, p = 0.001). More patients than controls reported smoking and fewer patients reported snuff use.
In this Norwegian MS case-control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, ...especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease 99 females, mean age: 41 (±14) years, median EDSS: 2 (0–7.5), 162 with AQP4-neuromyelitis optica spectrum disorder 132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0–8), 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0–8) and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson’s fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice.
In a multicentre MAGNIMS study, Cortese et al. show that brain and cord lesion characteristics on conventional MRI, together with clinical features, can help differentiate non-acute MOG-antibody disease from AQP4-NMOSD and multiple sclerosis, aiding identification of non-acute patients for MOG antibody testing.
To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum ...disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease.
A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported.
We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm
); AQP4+NMOSD in the occipital cortex (32.83 cm
); and RRMS diffusely in the GM (260.61 cm
). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm
), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm
). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm
) and AQP4+NMOSD (47.04 cm
). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation.
GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024.
Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The ...aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA).
We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years.
In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score ≤ -2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers.
Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the ...SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid position 52 in TSAd. The GA16 –rs926103⁎ A haplotype was associated with MS in Norwegians (OR 1.4, P = 0.04). A similar trend was observed among Danes. In the independent Norwegian, Danish and Swedish sample sets the GA16 allele showed a combined OR of 1.13, P = 0.05. Thus, the present study shows that the SH2D2A gene may contribute to susceptibility to MS.
We have investigated the genetic involvement of the
CD4 and the
LAG3 genes, two appealing candidates for MS due to their suggested role in MS pathology. We genotyped a Swedish case–control material ...consisting of 920 MS patients and 778 controls in an initial study of
CD4, three SNPs showed a significant association with MS. An independent material consisting of 1720 Nordic MS patients and 1416 controls were used for confirmation of associated markers in
CD4 and to do a confirmative study of the
LAG3 gene from previous findings. The result, including a total of 2640 MS patients and 2194 controls shows no significant association with
CD4 and
LAG3 and MS. We conclude that these genes are of minor importance in regard of genetic predisposition to the MS.
A recent study by Wang et al. (2016a) claims that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause multiple sclerosis in certain individuals and determines a patient’s likelihood of ...primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al. (2016a), but we find no evidence that this variant is associated with either MS or disease subtype. Wang et al. (2016a) also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS—of which no examples exist—can therefore not be substantiated by data. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by Minikel and MacArthur (2016) and the response by Wang et al. (2016b), published in this issue.
•We attempt to replicate Wang et al.’s observation that NR1H3 p.Arg415Gln drives multiple sclerosis risk•In a 13-fold larger sample, we find no evidence of association to either MS risk or clinical course•We conclude their result is a false positive due to insufficient statistical rigor and flawed logic
The IMSGC find no evidence in >69,000 samples that NR1H3 p.Arg415Gln causes multiple sclerosis in families and determines clinical course, as reported by Wang et al. This refutes the initial claim that NR1H3 mutations describe a Mendelian form of MS.
Chromosome region 2q33 encodes several regulators of the immune system, among these the
CD28,
CTLA4, and
ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We ...investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the
CD28/
CTLA4/
ICOS gene region.
Familial clustering of autoimmune disease is well recognized and raises the possibility that some susceptibility genes may predispose to autoimmunity in general. In light of this observation, it ...might be expected that some of the variants of established relevance in one autoimmune disease may also be relevant in other related conditions. On the basis of this hypothesis, we tested seven single nucleotide polymorphisms (SNPs) that are known to be associated with type I diabetes in a large multiple sclerosis data set consisting of 2369 trio families, 5737 cases and 10,296 unrelated controls. Two of these seven SNPs showed evidence of association with multiple sclerosis; that is rs12708716 from the CLEC16A gene (P=1.6 x 10(-16)) and rs763361 from the CD226 gene (P=5.4 x 10(-8)). These findings thereby identify two additional multiple sclerosis susceptibility genes and lend support to the notion of autoimmune susceptibility genes.
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