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Multiple sclerosis (MS) unfavorably affects working capacity. The Comprehensive International Classification of Functioning, Disability and Health Core Set for MS (cICF-MS), issued by the World Health Organization, has not yet been extended to evaluate working capacity level (WCL). To evaluate the relative importance of cICF-MS categories in relation to WCL. Persons with MS (PwMS), N = 129, who had been referred to Lithuania's Disability and Working Capacity Assessment Office for WCL determination, were divided into three groups according to the percentage of remaining WCL (WCL1 had 0-25%, WCL2 had 30-40%, and WCL3 had 45-55%). Data regarding the cICF-MS categories were collected through telephone interviews and patient documentation. Using the fractional ranking method, the mean values of cICF-MS impairment were ranked from the most severely affected to the least affected (rank 1-93). Ranks with the 10 highest mean values of impairment severity in each WCL group were included in a descriptive analysis. In the WCL1 and WCL2 groups, the most-affected cICF-MS categories reflected disability related to gait and motor function. The WCL3 group presented with pain, fatigue, and impairments to visual acuity, psychic stability, urination, and memory. This study has identified specific cICF-MS impairment profiles based on remaining WCL., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system and is triggered by several environmental factors in genetically predisposed people., Objectives: To explore which evaluation battery items used for evaluation of work capacity at baseline can best predict MS progression at 1 year follow-up., Methods: In this prospective single-centre study, participants with MS were recruited consecutively when visiting a neurologist for referral for the determination work capacity status at the Disability and Working Capacity Assessment Office. At baseline, a neurologist assessed patients using the following evaluation scales: Fatigue self-assessment, Fatigue Descriptive Scale (FDS), Memory self-assessment, Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), Short Form 36 (SF-36), and the Brief International Classification of Functioning and Disability (ICF) core set for MS. The Expanded Disability Status Scale (EDSS) was evaluated by neurologists at baseline and one year later. An increase in EDSS by 0.5 points after one year was defined as MS progression., Results: During the one year period among 72 participants, 21 fulfilled the criteria for MS progression. In more than 75% of these participants, impairments were found in the following ICF subitems at baseline: "energy and drive functions", "muscle and power functions", and "moving around". Greater impairments were identified in progressing participants. Progressing participants scored higher on the FDS and scored lower on the BICAMS and SF-36. Regression analysis indicated that the FDS sum score predicted MS progression one year later., Conclusions: Increased fatigue might indicate worsening in MS one year later., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Microglia are specialized dynamic immune cells in the central nervous system (CNS) that plays a crucial role in brain homeostasis and in disease states. Persistent neuroinflammation is considered a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (MS). Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models. Research using CSF-1R inhibitors has now been extended into non-human primates and humans. This review article summarizes the most recent advances using CSF-1R inhibitors in different neurodegenerative conditions including AD, PD, HD, ALS and MS. Potential challenges for translating these findings into clinical practice are presented., (© 2022. The Author(s).)

To investigate whether cerebrospinal fluid (CSF) markers differ between pediatric-onset multiple sclerosis (PoMS, onset < 18 years) and adult-onset (AoMS), and whether these markers are associated with clinical outcomes among PoMS. Prospective nationwide registry study of incident MS, including persons with a CSF sample < 3 years post-MS onset. We compared CSF oligoclonal band (OCB) status, immunoglobulin G (IgG) index levels, and mononuclear cell count between PoMS and AoMS. Within the PoMS cohort we analyzed the association between CSF markers, relapse rate and Expanded Disability Status Scale (EDSS) score, using negative binomial regression and generalized estimating equations, respectively. The cohort consisted of 130 PoMS and 3228 AoMS cases. The PoMS group had higher odds of OCB-positivity (odds ratio: 2.70; 95% CI 1.21-7.67). None of the CSF markers were associated with relapse rate in the PoMS cohort; however, OCB-positivity was associated with higher EDSS scores. This study suggested that PoMS more commonly display CSF evidence for intrathecal IgG production than AoMS. Further, we found evidence of a relationship between OCB-positivity and subsequent disability, suggesting that they could play a role in the prognostication of MS in children., (© 2021. The Author(s).)

Multiple sclerosis (MS) patients with immunoglobulin gamma (IgG) oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) have different genetic backgrounds and brain MRI features compared to those without. In this study, we aimed to determine whether CSF-OCB status is associated with long-term disability outcomes. We used Swedish MS register data on clinically definite MS patients with known OCB status. Date of birth, age at MS onset, and time to sustained Expanded Disability Status Scale (EDSS) milestones 3, 4, and 6; time to conversion to secondary progressive (SP) MS, sex, and immunomodulatory treatment (IMTs) duration were collected. Multivariate Cox regression models were used to investigate the association between OCB status and risk of reaching each milestone. The OCB-positive group reached disability milestones at an earlier time and younger age. OCB-positivity significantly increased the risk of reaching EDSS 3.0 (HR = 1.29, 95% CI 1.12 to 1.48, P < 0.001) and 4.0 (HR = 1.38, 95% CI 1.17 to 1.63, P < 0.001). The OCB-positive group had a 20% higher risk of conversion to SPMS. CSF-OCB presence is associated with higher risk of reaching EDSS milestones and conversion to SPMS. Our findings suggest higher disease modifying effect of OCB presence in the early inflammatory stages of MS., (© 2021. The Author(s).)

Background: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult., Objective: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes., Methods: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists., Results: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data., Conclusion: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information.

CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by colony stimulating factor 1 receptor (CSF1R) gene mutations. The disease has a global distribution and currently has no cure. Individuals with CSF1R-related leukoencephalopathy variably present clinical symptoms including cognitive impairment, progressive neuropsychiatric and motor symptoms. CSF1R is predominantly expressed on microglia within the central nervous system (CNS), and thus CSF1R-related leukoencephalopathy is now classified as a CNS primary microgliopathy. This urgent unmet medical need could potentially be addressed by using microglia-based immunotherapies. With the rapid recent progress in the experimental microglial research field, the replacement of an empty microglial niche following microglial depletion through either conditional genetic approaches or pharmacological therapies (CSF1R inhibitors) is being studied. Furthermore, hematopoietic stem cell transplantation offers an emerging means of exchanging dysfunctional microglia with the aim of reducing brain lesions, relieving clinical symptoms and prolonging the life of patients with CSF1R-related leukoencephalopathy. This review article introduces recent advances in microglial biology and CSF1R-related leukoencephalopathy. Potential therapeutic strategies by replacing microglia in order to improve the quality of life of CSF1R-related leukoencephalopathy patients will be presented.

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and, to a large extent, unknown pathophysiology. Structural brain differences, such as global or focal reductions in grey or white matter volumes, as well as enlargement of the sulci and the ventricles, have repeatedly been observed in individuals with AN. However, many of the documented aberrances normalize with weight recovery, even though some studies show enduring changes. To further explore whether AN is associated with neuronal damage, we analysed the levels of neurofilament light chain (NfL), a marker reflecting ongoing neuronal injury, in plasma samples from females with AN, females recovered from AN (AN-REC) and normal-weight age-matched female controls (CTRLS). We detected significantly increased plasma levels of NfL in AN vs CTRLS (median AN  = 15.6 pg/ml, IQR AN  = 12.1-21.3, median CTRL  = 9.3 pg/ml, IQR CTRL  = 6.4-12.9, and p < 0.0001), AN vs AN-REC (median AN-REC  = 11.1 pg/ml, IQR AN-REC  = 8.6-15.5, and p < 0.0001), and AN-REC vs CTRLS (p = 0.004). The plasma levels of NfL are negatively associated with BMI overall samples (β (±se) = -0.62 ± 0.087 and p = 6.9‧10 -12 ). This indicates that AN is associated with neuronal damage that partially normalizes with weight recovery. Further studies are needed to determine which brain areas are affected, and potential long-term sequelae.

Background: In multiple sclerosis various aspects of cognitive function can be detrimentally affected. More than that, patients´ employment and social functioning is likely to be impacted., Objective: To determine whether work disability among multiple sclerosis patients could be predicted by the symbol digit modalities test., Methods: A register-based cohort study was conducted. Individual data on work disability, operationalised as annual net days of sickness absence and/or disability pension were retrieved at baseline, when the symbol digit modalities test was performed, after one-year and 3-year follow-up for 903 multiple sclerosis patients. The incidence rate ratios for work disability were calculated with general estimating equations using a negative binomial distribution and were adjusted for gender, age, educational level, family composition, type of living area and physical disability., Results: After one year of follow-up, the patients in the lowest symbol digit modalities test quartile were estimated to have a 73% higher rate of work disability when compared to the patients in the highest symbol digit modalities test quartile (incidence rate ratio 1.73, 95% confidence interval 1.42‒2.10). This estimate after 3-year follow-up was similar (incidence rate ratio 1.68, 95% confidence interval 1.40‒2.02)., Conclusion: Cognitive function is to a high extent associated with multiple sclerosis patients' future work disability, even after adjusting for other factors.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care., (© 2016 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Background and Purpose: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony-stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This study's aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls., Methods: Five HDLS patients with c.2562T>A p.Asn854Lys CSF1R mutation, five age- and gender-matched MS patients and five healthy controls were cross-sectionally studied. All patients were examined neurologically. HDLS patients underwent Mini-Mental State Examination (MMSE). Brain MRI scans were analyzed volumetrically with FreeSurfer and Lesion Segmentation Toolbox and neuroradiologically with the brain MRI scoring system for HDLS., Results: Patients with HDLS had lower brain, grey matter and WM fractions (66.3%; 37.9%; 27.6%) compared with controls (78.5%, P = 0.008; 44.4%, P = 0.008; 32.0%, P = 0.008), but not compared with MS patients (65.7%, P = 0.7; 36.8%, P = 0.4; 27.3%, P = 0.7). Cerebellar WM changes and atrophy were not seen in the HDLS group. The HDLS lesion volume fraction correlated with MMSE scores (r = -0.90, P = 0.04)., Conclusions: Brain volume fractions in HDLS were lower than in controls and similar to those seen in MS. The cerebellum was relatively spared in HDLS, which may help in differentiating HDLS WM changes from MS. The strong relationship of HDLS lesions with MMSE scores indicates that accumulating WM pathology in HDLS is associated with cognitive decline., (© 2016 EAN.)

Background: Natalizumab therapy reduces inflammation and degeneration of the CNS in relapsing-remitting multiple sclerosis (RRMS). In cerebrospinal fluid (CSF) the concentration of 24S-hydroxycholesterol (24OHC) reflect neurodegeneration, whereas 27-hydroxycholesterol (27OHC) is dependent on the integrity of the blood-brain barrier (BBB)., Objective: To measure the impact from natalizumab treatment on 24OHC and 27OHC concentrations in serum and CSF of RRMS., Methods: In serum and CSF obtained from 31 patients before and following 12 months of natalizumab treatment, 24OHC and 27OHC were analyzed by isotope-dilution mass spectrometry., Results: Natalizumab treatment reduced CSF-24OHC concentrations (p=0.002), CSF-27OHC concentrations (p=0.01) and serum-24OHC concentrations (p=0.029). There was no significant effect of the treatment on serum-27OHC concentrations. Serum concentrations of 24OHC correlated with Symbol Digit Modalities Test scores before (r=0.5, p=0.007) and after natalizumab treatment (r=0.403, p=0.033)., Conclusions: We showed for the first time that natalizumab treatment of RRMS reduced the concentrations of 24- and 27OHC in CSF, indicating reduced neurodegeneration and improved integrity of the BBB, respectively. Our results imply a role for serum 24OHC as a biomarker of cognition (visuo-spatial ability and processing speed) in RRMS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Approximately 95% of Nordic multiple sclerosis (MS) patients display oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid. From a cohort of 2094 MS patients we retrieved well-characterized data from 40 OCB-negative and 60 OCB-positive patients, in an effort to determine whether lesion load on brain magnetic resonance imaging is affected by OCB status and carriage of HLA-DRB1*15 or HLA-DRB1*04. Positivity for OCB did not increase the risk of belonging to higher-lesion-load groups; nor did carrying HLA-DRB1*15 or HLA-DRB1*04. A trend was seen, however, whereby OCB positivity conferred a two-fold risk of displaying higher lesion loads infratentorially., (Copyright © 2012 Elsevier B.V. All rights reserved.)

With the purpose of demonstrating the use of positron emission tomography (PET) and radiolabelled glia markers to indicate regional cerebral damage, we measured with PET in four young multiplex sclerosis (MS) patients in two consecutive measurements the global and regional brain uptake as well as regional distribution and binding potential (BP) of [(11)C]vinpocetine and [(11)C]PK11195. Both ligands showed increased uptake and BP in the regions of local brain damage. However, regional BP values for [(11)C]vinpocetine were markedly higher than those for [(11)C]PK11195. This feature of the former radioligand may be related to its high brain uptake and marked affinity to the peripheral benzodiazepine receptor binding sites (PBBS), characteristic for glia cells. As local brain traumas entail reactive glia accumulation in and around the site of the damage, the present findings may indicate that [(11)C]vinpocetine marks the place or boundaries of local brain damage by binding to the PBBS present in glia cells, which, in turn, accumulate in the region of the damage. The present findings (i) confirm earlier observations with [(11)C]PK11195 as a potential glia marker in PET studies and (ii) support the working hypothesis that [(11)C]vinpocetine is a potentially useful PET marker of regional and global brain damage resulting in glia accumulation locally or globally in the human brain. The comparative analysis of the two ligands indicate that [(11)C]vinpocetine shows a number of characteristics favourable in comparison with [(11)C]PK11195.

Objectives: The concentration in plasma of the brain-specific cholesterol metabolite cerebrosterol has been proposed as a biomarker of neurodegeneration in multiple sclerosis (MS) and other neurological diseases. It is unknown, however, which pathophysiological process in MS best accounts for variations in plasma cerebrosterol., Patients and Methods: In this study, we related plasma cerebrosterol concentrations in 46 MS patients - 27 with a relapsing-remitting (RR) disease course and 19 with a primary progressive (PP) course - to three conventional magnetic resonance imaging measures: on T(1)-weighted brain scans, volume of gadolinium-enhanced lesions (a marker of active inflammation) and hypointense lesions (a marker of edema or axonal loss) and on T(2)-weighted scans, volume of hyperintense lesions (a marker of disease extent)., Results: By multiple-regression analysis, we uncovered negative correlations between the cerebrosterol-cholesterol ratio in plasma and both age at sampling (beta=-0.35 and p=0.079 in RRMS; beta=-0.76 and p=0.006 in PPMS) and volume of T(2)-weighted lesions (beta=-0.52 and p=0.078 in RRMS; beta=-0.50 and p=0.247 in PPMS)., Conclusion: We hypothesize that decreases in plasma cerebrosterol may reflect the total spatiotemporal burden of MS-the cumulative effects of its dissemination in space and its duration in time.

B cells play an indispensable, yet indeterminate, role in the pathogenesis of multiple sclerosis (MS). We measured mRNA of APRIL-a promotor of B-cell survival-in peripheral blood and quantified protein levels in plasma and cerebrospinal fluid in MS patients and controls. APRIL mRNA levels in monocytes and T cells were significantly higher in MS patients than in controls. Levels of soluble APRIL in plasma were higher in patients with chronic progressive MS than in patients with relapsing-remitting MS, albeit not significantly. MS may thus be associated with increased transcription in peripheral blood of factors promoting B-cell survival, including APRIL.