Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent... Show moreMultiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/ inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immunemodulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, CARNS1 is not required for normal oligodendrocyte precursor cell differentiation and (re) myelin to occur, and neither endogenous nor exogenous HCDs protect against cuprizone-induced demyelination. In conclusion, the loss of CARNS1 from demyelinated MS lesions can aggravate disease progression through weakening the endogenous protection against neuroinflammation. Show less
The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and... Show moreThe imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS. Show less
This thesis has described novel synthetic methods to produce a variety of (glyco)peptides and their application in the study of various immunological processes. The first part of the thesis... Show moreThis thesis has described novel synthetic methods to produce a variety of (glyco)peptides and their application in the study of various immunological processes. The first part of the thesis describes novel insights into the pathogenesis of multiple sclerosis, in the form of new findings in the areas of lectin-driven immunotolerance and a biochemical comparison between human and animal model antigen. The next part describes novel multivalently glycosylated peptides, that can be used to study lectin binding and lectin mediated antigen uptake. The final part of the thesis describes a novel method to produce trans-cyclooctene protected peptides, an exciting new category of molecular tools within chemical biology that have recently been developed. Show less
Hiele, K. van der; Egmond, E.E.A. van; Gorp, D.A.M. van; Jongen, P.J.; Reneman, M.F.; Klink, J.J.L. van der; ... ; Visser, L.H. 2022
Previous research discovered a protective effect of higher conscientiousness against a 3-year deterioration in employment status in persons with multiple sclerosis (pwMS). To replicate these... Show morePrevious research discovered a protective effect of higher conscientiousness against a 3-year deterioration in employment status in persons with multiple sclerosis (pwMS). To replicate these findings, we used data from a multicentre prospective cohort study where 145 employed pwMS completed questionnaires, neurological and neuropsychological examinations at baseline and after 3 years. A 3-year deterioration in employment status was reported in 31.0%. We observed no differences in personality, demographics or clinical characteristics between pwMS with deteriorated or stable employment status. These null findings may be partly explained by the classification of deteriorated employment status, which does not reflect Dutch labour conditions. Show less
Egmond, E.E.A. van; Gorp, D.A.M. van; Jongen, P.J.; Klink, J.J.L. van der; Reneman, M.F.; Arnoldus, E.P.J.; ... ; Hiele, K. van der 2021
Purpose This study aimed to identify mental health, physical health, demographic and disease characteristics relating to work productivity in people with multiple sclerosis (MS). Methods In this... Show morePurpose This study aimed to identify mental health, physical health, demographic and disease characteristics relating to work productivity in people with multiple sclerosis (MS). Methods In this cross-sectional study, 236 employed people with MS (median age = 42 years, 78.8% female) underwent neurological and neuropsychological assessments. Additionally, they completed questionnaires inquiring about work productivity (presenteeism: reduced productivity while working, and absenteeism: loss of productivity due to absence from work), mental and physical health, demographic and disease characteristics. Multiple linear and logistic regression analyses were performed with presenteeism and absenteeism as dependent variables, respectively. Results A model with mental and physical health factors significantly predicted presenteeism F(11,202) = 11.33, p < 0.001, R-2 = 0.38; a higher cognitive (p < 0.001) and physical impact (p = 0.042) of fatigue were associated with more presenteeism. A model with only mental health factors significantly predicted absenteeism; chi(2)(11)=37.72, p < 0.001, with R-2 = 0.27 (Nagelkerke) and R-2 = 0.16 (Cox and Snell). Specifically, we observed that more symptoms of depression (p = 0.041) and a higher cognitive impact of fatigue (p = 0.011) were significantly associated with more absenteeism. Conclusions In people with MS, both cognitive and physical impact of fatigue are positively related to presenteeism, while symptoms of depression and cognitive impact of fatigue are positively related to absenteeism. Show less
Hiele, K. van der; Gorp, D.A.M. van; Egmond, E.E.A. van; Jongen, P.J.; Reneman, M.F.; Klink, J.J.L. van der; ... ; Visser, L.H. 2021
Background: Multiple sclerosis (MS) poses a major threat to sustainable employability. Identifying conditions and factors that promote work participation is of great importance. Our objective was... Show moreBackground: Multiple sclerosis (MS) poses a major threat to sustainable employability. Identifying conditions and factors that promote work participation is of great importance. Our objective was to explore the contribution of personality traits in explaining occupational functioning in MS. Methods: 241 participants with relapsing-remitting MS (78% female, median age: 42.0 years, median EDSS: 2.0) and 60 healthy controls (70% female, median age: 45.0 years) underwent neuropsychological and neurological examinations and completed questionnaires. Multivariate logistic and linear regression analyses were conducted to examine relations between personality traits and self-reported occupational functioning, while accounting for known correlates. Results: Personality traits were not associated with self-reported occupational functioning when correcting for known correlates. A higher impact of fatigue (B = -0.05, p = .005 and B = -0.04, p = .009) and depression (B = -0.22, p = .008 and B = -0.21, p = .01) were associated with no paid job (R2 = 0.13) and considering to reduce work hours (R2 = 0.12). A higher impact of fatigue (B = -0.05, p = .008, beta = 0.46, p = .001 and beta = -0.36, p = .001) was associated with absenteeism from work (R2 = 0.15), more presenteeism (R2 = 0.35) and lower work ability (R2 = 0.25). A higher impact of fatigue (beta = 0.46, p = .001) and anxiety (beta = 0.25, p = .001) were associated with more work difficulties (R2 = 0.54). Conclusion: Personality traits did not explain additional variance in self-reported occupational functioning in persons with relapsing-remitting MS with mild disability. The impact of fatigue was the main and most consistent correlate of occupational functioning, often combined with depression or anxiety. Total explained variance of the Show less
Hiele, K. van der; Egmond, E.E.A. van; Jongen, P.J.; Klink, J.J.L. van der; Beenakker, E.A.C.; Eijk, J.J.J. van; ... ; Visser, L.H. 2020
Background: Recent studies report deficits in social cognition in individuals with multiple sclerosis (MS). Social cognitive skills such as empathy are important for adequate social and... Show moreBackground: Recent studies report deficits in social cognition in individuals with multiple sclerosis (MS). Social cognitive skills such as empathy are important for adequate social and occupational functioning. Our objectives are: (1) to examine whether empathy differs between individuals with MS and healthy controls, (2) to examine relations between empathy and cognitive, psychological and occupational functioning. Methods: 278 individuals with MS (relapsing-remitting subtype) and 128 healthy controls from the MS@Work study participated in this investigation. The participants completed questionnaires about demographics, cognitive, psychological and occupational functioning, and underwent neurological and neuropsychological examinations. Mann-Whitney U-tests were used to examine group differences in empathy. Pearson and Spearman rank correlation analyses were used to examine relations between empathy and the other measures. Results: Empathy did not differ between individuals with MS and healthy controls. In individuals with MS, higher empathy was correlated with a higher educational level (X-2(df) = 13.2(2), p = 0.001), better verbal learning (r = 0.20, p = 0.001), less symptoms of depression (r=-0.21, p = 0.001), higher extraversion (r = 0.25, p <= 0.001), agreeableness (r = 0.55, p <= 0.001) and conscientiousness ( r = 0.27, p <= 0.001) and better occupational functioning in terms of work scheduling and output demands (r = 0.23, p = 0.002) and less cognitive/psychological work barriers (r = -0.21, p = 0.001). In healthy controls, higher empathy was correlated with less symptoms of depression (r = -0.34, p <= 0.001), less fatigue (r = -0.37, p <= 0.001), higher agreeableness (r = 0.59, p <= 0.001) and better occupational functioning in terms of work ability as compared to lifetime best (r = 0.28, p = 0.001) and less cognitive/psychological work barriers (r = -0.34, p <= 0.001). Empathy did not differ between unemployed and employed individuals with MS or healthy controls. Conclusion: Empathy did not differ between individuals with MS and healthy controls. Within both investigated groups, higher empathy was weakly to moderately correlated with less symptoms of depression, higher agreeableness and better occupational functioning. We also found unique correlations for empathy within the investigated groups. Longitudinal studies are needed to further examine social cognition in relation to cognitive, psychological and occupational functioning in both individuals with MS and healthy controls. It would be particularly interesting to concurrently examine changes in the brain network involved with social cognition. Show less
This thesis describes six clinical studies: two studies that investigate new compounds to treat symptoms of multiple sclerosis (MS) (chapters 2 and 3), one study that investigates a new... Show moreThis thesis describes six clinical studies: two studies that investigate new compounds to treat symptoms of multiple sclerosis (MS) (chapters 2 and 3), one study that investigates a new compound to treat MS (chapter 4) and three studies about the development of new methods to determine effects of a new class of compounds to treat MS (chapters 5, 6 and 7). Show less
Lee, S.J. van der; Conway, O.J.; Jansen, I.; Carrasquillo, M.M.; Kleineidam, L.; Akker, E. van den; ... ; GIFT Genetic Invest 2019
Background: Cognitive dysfunction is increasingly being recognized as an important limiting factor in work participation in patients with multiple sclerosis. This literature review provides a... Show moreBackground: Cognitive dysfunction is increasingly being recognized as an important limiting factor in work participation in patients with multiple sclerosis. This literature review provides a description, synthesis and interpretation of the existing literature and identifies gaps in current knowledge.Methods: Papers published between 1970 and April 2017 were included. Clinical trials, randomized controlled trials or observational quantitative studies in which data on cognitive factors associated with employment, work functioning or work-related problems were reported. Papers were manually double checked by two blinded reviewers.Results: A total of 41 papers were included of which 4 described prospective, longitudinal studies. The majority of studies reported positive associations between cognitive functioning and work outcomes (38/41 studies; 93%). Positive associations were found between work outcomes and global cognitive functioning (8/9 studies; 89%), language (8/17 studies; 47%), processing speed/ working memory (23/26 studies; 88%),new learning and memory (12/22 studies; 55%), executive functioning (10/17; 59%), intelligence (1/6; 17%) and self-reported cognitive functioning (14/15; 93%). None of the reviewed studies found a relation between visuospatial processing and work outcomes (0/8; 0%). Models including cognitive measures as well as demographic (age, education), neurological (disability, fine motor coordination, disease course), and psychological variables (depression, personality, fatigue) best predicted work outcomes.Conclusion: By conducting this review we found ample evidence that objective cognitive functioning (specifically processing speed/ working memory and executive functioning) and self-reported cognitive functioning are important independent associates of work outcomes and these factors should be addressed by healthcare professionals. Future research could benefit from a focus on longitudinal changes in cognition and its relation to work outcomes. Show less
Kallweit, U.; Bassetti, C.L.A.; Oberholzer, M.; Fronczek, R.; Beguin, M.; Strub, M.; Lammers, G.J. 2018
