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1.
  • Novakova, Lenka, 1984, et al. (author)
  • Cerebrospinal fluid sulfatide isoforms lack diagnostic utility in separating progressive from relapsing-remitting multiple sclerosis.
  • 2023
  • In: Multiple sclerosis and related disorders. - 2211-0356. ; 74
  • Journal article (peer-reviewed)abstract
    • Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system. The glycosphingolipid sulfatide, a lipid particularly enriched in the myelin sheath, has been shown to be involved the maintenance of this specific membrane structure. Sulfatide in cerebrospinal fluid (CSF) may reflect demyelination, a dominating feature of MS. We investigated the diagnostic utility of CSF sulfatide isoform levels to separate different courses or phenotypes of MS disease.This was a mono-center, cross-sectional study of relapsing-remitting MS (RRMS) (n=45) and progressive MS (PMS) (n=42) patients (consisting of primary PMS (n=17) and secondary PMS (n=25)) and healthy controls (n=19). In total, 20 sulfatide isoforms were measured in CSF by liquid chromatography-mass spectrometry.CSF total sulfatide concentrations, as well as CSF sulfatide isoform distribution, did not differ across the study groups, and their levels were independent of disease course/phenotype, disease duration, time to conversion to secondary PMS, age, and disability in MS patients.CSF sulfatide isoforms lack diagnostic and prognostic utility as a biomarker for progressive MS.
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2.
  • Novakova, Lenka, 1984, et al. (author)
  • Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing-remitting MS
  • 2018
  • In: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 146:3, s. 322-332
  • Journal article (peer-reviewed)abstract
    • Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Several biomarkers including proteins and lipids have been reported in MS cerebrospinal fluid (CSF), reflecting different aspects of the pathophysiology particularly of relapsing-remitting MS (RRMS). Sulfatide, abundant in the myelin sheath and a proposed target for autoimmune attack in MS, has been reported altered in MS CSF. Here, we investigated the potential of CSF sulfatide and its isoforms as biomarkers in MS. A highly sensitive and quantitative mass spectrometry method was employed to determine levels of sulfatide isoforms in CSF from RRMS and progressive MS (PMS) patients, and healthy donors (HD). We demonstrate that levels of total CSF sulfatide and C24:1, C26:1, and C26:1-OH isoforms were significantly increased in PMS compared with RRMS patients and HD, while C23:0-OH was significantly decreased in CSF from PMS patients compared to the other two groups. Multivariate discriminant analysis showed that CSF sulfatide isoform pattern in PMS patients was distinct and non-overlapping with that of RRMS patients and HD. Sulfatide levels did not correlate with tested biomarkers or clinical parameters. The results suggest that CSF sulfatide isoform levels may be used to discriminate the phenotype ofMS and might play a role in the progression of the disease.
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3.
  • Stevens-Jones, Oskar, et al. (author)
  • Presence of neural surface and onconeural autoantibodies in cerebrospinal fluid and serum in neurological diseases presents a potential risk for misdiagnosis
  • 2023
  • In: European Journal of Neurology. - 1351-5101. ; 30:9, s. 2602-2610
  • Journal article (peer-reviewed)abstract
    • Background and purpose: Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not.Methods: We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants.Results: Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older.Conclusions: The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.
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4.
  • Akel, Sarah, et al. (author)
  • Neurofilament light, glial fibrillary acidic protein, and tau in a regional epilepsy cohort: High plasma levels are rare but related to seizures
  • 2023
  • In: Epilepsia. - 0013-9580. ; 64:10, s. 2690-2700
  • Journal article (peer-reviewed)abstract
    • Objective: Higher levels of biochemical blood markers of brain injury have been described immediately after tonic-clonic seizures and in drug-resistant epilepsy, but the levels of such markers in epilepsy in general have not been well characterized. We analyzed neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau in a regional hospital-based epilepsy cohort and investigated what proportion of patients have levels suggesting brain injury, and whether certain epilepsy features are associated with high levels.Methods: Biomarker levels were measured in 204 patients with an epilepsy diagnosis participating in a prospective regional biobank study, with age and sex distribution correlating closely to that of all patients seen for epilepsy in the health care region. Absolute biomarker levels were assessed between two patient groups: patients reporting seizures within the 2 months preceding inclusion and patients who did not have seizures for more than 1 year. We also assessed the proportion of patients with above-normal levels of NfL.Results: NfL and GFAP, but not tau, increased with age. Twenty-seven patients had abnormally high levels of NfL. Factors associated with such levels were recent seizures (p = .010) and epileptogenic lesion on radiology (p = .001). Levels of NfL (p = .006) and GFAP (p = .032) were significantly higher in young patients (<65 years) with seizures & LE;2 months before inclusion compared to those who reported no seizures for >1 year. NfL and GFAP correlated weakly with the number of days since last seizure (NfL: r(s) = -.228, p = .007; GFAP: r(s) = -.167, p = .048) in young patients. NfL also correlated weakly with seizure frequency in the last 2 months (r(s) = .162, p = .047).Significance: Most patients with epilepsy do not have biochemical evidence of brain injury. The association with seizures merits further study; future studies should aim for longitudinal sampling and examine whether individual variations in NfL or GFAP levels could reflect seizure activity.
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5.
  • Alping, P., et al. (author)
  • Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients
  • 2016
  • In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:6, s. 950-958
  • Journal article (peer-reviewed)abstract
    • Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy. Methods: We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umea, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%). Results: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center). Interpretation: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns.
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6.
  • Ashton, Nicholas J., et al. (author)
  • A multicentre validation study of the diagnostic value of plasma neurofilament light
  • 2021
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
  • Journal article (peer-reviewed)abstract
    • Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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7.
  • Augutis, Kristin, et al. (author)
  • Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis.
  • 2013
  • In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:5, s. 543-52
  • Journal article (peer-reviewed)abstract
    • Amyloid precursor protein (APP) and amyloid β (Aβ) peptides are intensely studied in neuroscience and their cerebrospinal fluid (CSF) measurements may be used to track the metabolic pathways of APP in vivo. Reduced CSF levels of Aβ and soluble APP (sAPP) fragments are reported in inflammatory diseases, including multiple sclerosis (MS); but in MS, the precise pathway of APP metabolism and whether it can be affected by disease-modifying treatments remains unclear.
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8.
  • Axelsson, Markus, 1975, et al. (author)
  • Cerebrospinal fluid NCAM levels are modulated by disease-modifying therapies
  • 2019
  • In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 139:5, s. 411-427
  • Journal article (peer-reviewed)abstract
    • Background: Little is known about what leads to recovery between relapses in multiple sclerosis (MS), particularly following treatment. In the past, it has been demonstrated that soluble neural cell adhesion molecule (sNCAM), a putative biomarker of neuroplasticity, increased following steroid treatment in the Cerebrospinal fluid (CSF) of MS subjects undergoing acute relapses. Taking this a step further, we have evaluated the effect of disease-modifying treatment (DMTs) on CSF sNCAM levels in various subtypes of MS. Methods: We measured CSF sNCAM levels at baseline and after 12-24months of DMT in 69 patients, 49 relapsing-remitting MS (RRMS), 20 progressive MS(PMS), and 24 healthy controls (HC) using an in-house ELISA. Of this, 31 patients had received natalizumab, 17 mitoxantrone, and 21 fingolimod. Changes in disability were measured using EDSS and disease severity by MSSS. In conjunction, CSF NfL levels were also measured. Results: At baseline, the mean sNCAM level was 268.7ng/mL (SD: 109ng/mL) in MS patients compared with 340.6ng/ml (SD: 139ng/mL) in HC, and PMS had significantly lower sNCAM (239.2ng/mL, SD: 123.0, P=0.019) compared to RRMS (269.4, SD: 127.4, P=0.043). After natalizumab and mitoxantrone treatments, we observed an increase in mean sNCAM. However, in the fingolimod-treated group, mean sNCAM decreased. There was no correlation found with EDSS or MSSS, or NfL levels as a whole. Conclusions: Cerebrospinal fluid sNCAM levels were found to be lower in MS than in HC and the lowest sNCAM levels were found in PMS. Following natalizumab and mitoxantrone treatments, we observed an elevation in sNCAM levels, an effect that was not observed following fingolimod treatment. These changes, however, did not appear to correlate with disability in the short-term or NfL levels. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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9.
  • Axelsson, Markus, 1975, et al. (author)
  • Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis.
  • 2014
  • In: Multiple sclerosis (Houndmills, Basingstoke, England). - London, United Kingdom : SAGE Publications. - 1477-0970 .- 1352-4585. ; 20:1, s. 43-50
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression. OBJECTIVE: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13). METHODS: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays. RESULTS: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline. CONCLUSIONS: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.
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10.
  • Axelsson, Markus, 1975, et al. (author)
  • Neurofilament light protein levels in cerebrospinal fluid predict long-term disability of Guillain-Barré syndrome: A pilot study.
  • 2018
  • In: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 138:2, s. 143-150
  • Journal article (peer-reviewed)abstract
    • Although the recovery from Guillain-Barré syndrome (GBS) is good in most patients, some develop permanent severe disability or even die. Early predictors would increase the likelihood to identify patients at risk for poor outcome at the acute stage, allowing them intensified therapeutic intervention.Eighteen patients with a history of GBS 9-17years ago were reassessed with scoring of neurological disability and quality of life assessment (QoL). Their previous diagnostic work-up included clinical examination with scoring of disability, neurophysiological investigation, a battery of serology tests for infections, and cerebrospinal fluid (CSF) examination. Aliquots of CSF were frozen, stored for 20-28years, and analyzed by ELISA for determination of neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP).Patients with poor outcome (n=3) had significantly higher NFL and GFAP levels at GBS nadir than those with good outcome (n=15, P<.01 and P<.05, respectively). High NFL correlated with more prominent disability and worse QoL at long-term follow-up (r=.694, P<.001, and SF 36 dimension physical component summary (PCS) (r =-.65, P<.05), respectively, whereas GFAP did not correlate with clinical outcome or QoL.High NFL in CSF at the acute stage of GBS seems to predict long-term outcome and might, together with neurophysiological and clinical measures, be useful in treatment decisions and clinical care of GBS.
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11.
  • Axelsson, Markus, 1975, et al. (author)
  • The influence of disease duration, clinical course, and immunosuppressive therapy on the synthesis of intrathecal oligoclonal IgG bands in multiple sclerosis.
  • 2013
  • In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728. ; 264:1-2, s. 100-5
  • Journal article (peer-reviewed)abstract
    • We investigated the impact of disease duration, clinical course and immunosuppressive therapy on intrathecal IgG synthesis in multiple sclerosis (MS). Cerebrospinal fluid (CSF) was obtained twice, 8-10years apart, from 20 MS patients and 26 healthy controls, and from 22 MS patients before and after two years of mitoxantrone treatment. The oligoclonal IgG band patterns changed in 15 patients at long-term follow-up, but were only influenced in 4 patients by mitoxantrone therapy. The CSF B-cell-regulating chemokine CXCL13 correlated with intrathecal IgG production suggesting a B-cell-dependence of intrathecal IgG synthesis in MS.
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12.
  • Boremalm, Malin, et al. (author)
  • Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis
  • 2019
  • In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 26:8, s. 1060-1067
  • Journal article (peer-reviewed)abstract
    • Background and purpose Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS. Methods Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models. Results A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ. Conclusions In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.
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13.
  • Bridel, Claire, et al. (author)
  • Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
  • 2019
  • In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
  • Research review (peer-reviewed)abstract
    • Importance  Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives  To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources  PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection  Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis  Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure  The cNfL levels adjusted for age and sex across diagnoses.Results  Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance  These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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14.
  • Burman, Joachim, et al. (author)
  • YKL-40 is a CSF biomarker of intrathecal inflammation in secondary progressive multiple sclerosis.
  • 2016
  • In: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 292, s. 52-7
  • Journal article (peer-reviewed)abstract
    • YKL-40 (CHI3L1) is a glycoprotein predominantly produced by reactive astrocytes in chronic active MS lesions, which are common in secondary progressive MS. In this study, YKL-40 was investigated in different stages of MS and in relation to MRI findings. YKL-40 levels in CSF samples from two independent patient cohorts of MS patients were determined with ELISA. CSF YKL-40 was increased in patients with active relapsing-remitting MS and correlated with the number of gadolinium enhancing lesions. Patients with secondary progressive MS had similar high levels of YKL-40, whereas not active relapsing-remitting MS patients had YKL-40 levels comparable to healthy controls.
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15.
  • Constantinescu, Clara, 1995, et al. (author)
  • Persons with suspicious onset of multiple sclerosis but with undetermined diagnosis had persistent lower cognition and reduced quality of life
  • 2021
  • In: Multiple Sclerosis and Related Disorders. - : Elsevier BV. - 2211-0348. ; 52
  • Journal article (peer-reviewed)abstract
    • Backgound: Differential diagnosis of multiple sclerosis (MS) includes a variety of disorders and misdiagnosis is common. Objective: To follow-up persons with suspected onset of MS but in whom the diagnostic investigation was negative. Methods: In a prospective study including 271 persons with clinical features of suspected MS onset, 136 persons were diagnosed with MS or clinically isolated syndrome (PwMS), 46 had other disorders, and 89 persons had a negative diagnostic work-up, i.e. persons with undetermined diagnosis (PwUD). They underwent diagnostic reassessment, and those who remained without a diagnosis were investigated for signs of pathology including cognitive tests and assessments of quality of life (QoL). Results were compared with those of PwMS and 24 age and sex matched healthy controls (HC). Results: After reassement 55 (20%) persons still had undetermined diagnosis (PwUD). They had similar age and gender distribution as PwMS. In 76% of PwUD, the suspected clinical onset included sensory symptoms. PwUD and PwMS scored similarly in cognitive tests and QoL but significantly lower than HC. At 3 years follow-up, PwMS and PwUD improved in most test parameters, but PwUD scored lower than PwMS in cognition. Conclusion: PwUD constituted the dominating differential diagnosis in persons with suspected clinical onset of MS. QoL and cognition were comparable with those of PwMS but significantly lower than in HC.
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16.
  • Constantinescu, Radu, 1966, et al. (author)
  • Cerebrospinal fluid biomarkers in patients with neurological symptoms but without neurological diseases
  • 2019
  • In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404.
  • Journal article (peer-reviewed)abstract
    • Background: Elevated levels of the cerebrospinal fluid (CSF) neuronal injury markers (neurofilament light chain [NF-L] and total tau protein [t-tau]) and of the astroglial marker glial fibrillary acidic protein (GFAP) are found in etiologically different neurological disorders affecting the peripheral and the central nervous system. Aims: To explore the role of CSF biomarkers in the clinical management of patients admitted for alarming neurological symptoms, but in whom neurological disorders could be excluded. Methods: Study participants were patients seeking medical attention for neurological symptoms primarily considered to be caused by a neurological diagnosis and investigated according to clinical routine. Demographic, clinical, and CSF data were extracted retrospectively from medical records. Patients with a final neurological diagnosis were excluded. Results: Out of 990 patients, 900 with a neurological diagnosis were excluded leaving 90 patients without a final neurological diagnosis. Sixty-eight (75.6%) were females. Median (range) age at lumbar puncture was 34.7 (16.9-65.1)years. Age-adjusted CSF-NF-L, CSF-t-tau, and CSF-GFAP concentrations were normal in 89 (98.9%), 86 (95.6%), and 87 (96.7%) patients, respectively. Conclusion: In patients with significant neurological symptoms but in whom a neurological diagnosis could not be made, the CSF markers NF-L, t-tau, and GFAP did not indicate signs of neuronal or astroglial cell damage close to symptom onset. Consequently, increased levels of CSF markers are not expected in this patient group and, if present, should raise suspicion of underlying neurological disorders and motivate further investigations. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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17.
  • Constantinescu, Radu, 1966, et al. (author)
  • Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies.
  • 2017
  • In: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 306, s. 25-30
  • Journal article (peer-reviewed)abstract
    • Autoimmune neurologic syndromes can be paraneoplastic (associated with malignancies and/or onconeural antibodies), or non-paraneoplastic. Their clinical presentation is often similar. As prognosis is related to malignancy treatment, better biomarkers are needed to identify patients with malignancy. We investigated cerebrospinal fluid (CSF) markers of neuronal (neurofilament light chain, NFL and total tau protein, T-tau) and glial (glial fibrillary acidic protein) damage. CSF-NFL and T-tau were increased in both paraneoplastic and non-paraneoplastic autoimmune syndromes. Patients with manifest malignancies were older, had less epilepsy, more focal central and peripheral neurological signs and symptoms, and worse long-term outcome, than those without malignancy. CSF-NFL-levels predicted long-term outcome but were not diagnostic for malignancy, after age adjustment.
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18.
  • Constantinescu, Radu, 1966, et al. (author)
  • Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis
  • 2016
  • In: European Journal of Neurology. - : Wiley. - 1351-5101. ; 23:4, s. 796-806
  • Journal article (peer-reviewed)abstract
    • Background and purposeClinical symptoms and long-term outcome of autoimmune encephalitis are variable. Diagnosis requires multiple investigations, and treatment strategies must be individually tailored. Better biomarkers are needed for diagnosis, to monitor disease activity and to predict long-term outcome. The value of cerebrospinal fluid (CSF) markers of neuronal [neurofilament light chain protein (NFL), and total tau protein (T-tau)] and glial cell [glial fibrillary acidic protein (GFAP)] damage in patients with autoimmune encephalitis was investigated. MethodsDemographic, clinical, magnetic resonance imaging, CSF and antibody-related data of 25 patients hospitalized for autoimmune encephalitis and followed for 1 year were retrospectively collected. Correlations between these data and consecutive CSF levels of NFL, T-tau and GFAP were investigated. Disability, assessed by the modified Rankin scale, was used for evaluation of disease activity and long-term outcome. ResultsThe acute stage of autoimmune encephalitis was accompanied by high CSF levels of NFL and T-tau, whereas normal or significantly lower levels were observed after clinical improvement 1 year later. NFL and T-tau reacted in a similar way but at different speeds, with T-tau reacting faster. CSF levels of GFAP were initially moderately increased but did not change significantly later on. Final outcome (disability at 1 year) directly correlated with CSF-NFL and CSF-GFAP levels at all time-points and with CSF-T-tau at 3 1 months. This correlation remained significant after age adjustment for CSF-NFL and T-tau but not for GFAP. ConclusionIn autoimmune encephalitis, CSF levels of neuronal and glial cell damage markers appear to reflect disease activity and long-term disability.
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19.
  • Constantinescu, Radu, 1966, et al. (author)
  • Cerebrospinal fluid neurofilament light and tau protein as mortality biomarkers in parkinsonism
  • 2019
  • In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 140:2, s. 147-156
  • Journal article (peer-reviewed)abstract
    • - Background: Mortality is increased in parkinsonian disorders, moderately in Parkinson's disease (PD) but markedly in atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Still, there are no reliable quantitative biomarkers for mortality. The cerebrospinal fluid (CSF) neurodegeneration biomarkers such as neurofilament light chain (NF-L), total tau (t-tau), and the tau pathology marker phosphorylated tau (p-tau) are related to mortality in other neurological disorders (eg, amyotrophic lateral sclerosis, Alzheimer's disease), but have not been investigated in this respect in parkinsonian disorders. Aims: To investigate the CSF biomarkers' (NF-L, t-tau, and p-tau) relationship to mortality in parkinsonian disorders. Methods: Demographic, mortality, and CSF data were collected from 68 PD and 83 APD patients. Survival analysis was conducted using Cox regression, with age at lumbar puncture, gender, diagnosis, and levels of CSF biomarkers as predictors. Results: NF-L in CSF was associated with increased mortality in synucleinopathies (PD, MSA; HR 3.698 [2.196-6.228, 95% confidence interval (CI)], P<0.001), in PSP (HR 2.767 [1.126-6.802 95% CI], P=0.027), and in the entire cohort (HR 1.661 [1.082-2.55, 95% CI], P=0.02). t-Tau in CSF was associated with increased mortality in PSP (HR 9.587 [1.143-80.418], P=0.037). p-Tau in CSF was associated with decreased mortality in synucleinopathies (HR 0.196 [0.041-0.929, 95% CI], P=0.040). Atypical parkinsonian disorders and tauopathies were associated with higher mortality (HR 8.798 [4.516-17.14, 95% CI] and HR 3.040 [1.904-4.854], respectively, P<0.001). Conclusion: NF-L and tau protein in CSF might be useful for mortality prognosis in patients with parkinsonian disorders and should be investigated in larger studies. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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20.
  • Corderfeldt, Anna, et al. (author)
  • A prospective feasibility trial exploring novel biomarkers for neurotoxicity after isolated limb perfusion
  • 2023
  • In: Perfusion-Uk. - 0267-6591.
  • Journal article (peer-reviewed)abstract
    • Background: Isolated limb perfusion (ILP) is a regional cancer treatment in which high-dose chemotherapy is administered in an isolated extremity. The main side effect is regional toxicity, which occasionally leads to nerve damage. Measuring neuroaxonal biomarkers, might be a method predicting such complications. Therefore, the primary aim of the study is to investigate if neuronal biomarkers are measurable and alters in an isolated extremity during ILP. Secondly, if postoperative regional toxicity, alterations in sensitivity, and/or muscle strength are correlated to the biomarker levels.Methods: Eighteen scheduled ILP-patients were included in the study. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau concentrations were measured in plasma sampled preoperatively, at the start and end of the ILP, on days 3 and 30, using ultrasensitive Single molecule array (Simoa) technology. The patients were assessed by a physiotherapist pre- and postoperatively.Results: At ILP end, significantly higher NfL and tau levels were measured in the extremity than in the corresponding systemic circulation (NfL; 17 vs 6 ng/L, p < .01, tau; 1.8 vs 0.6 ng/L, p < .01), and the extremity levels were significantly increased at ILP end (NfL; 66 +/- 37%, p < .001, tau; 75 +/- 45%, p = .001). On days 3 and 30, significantly increased NfL and GFAP levels were measured systemically (NfL day 3: 69 +/- 30%, p < .001; day 30: 76 +/- 26%, p < .001; GFAP day 3: 33 +/- 22%, p < .002; day 30: 33 +/- 23%, p <= .004). Finally, no significant correlations were found between regional toxicity or between postoperative muscle or sensitivity decrease and biomarker release.Conclusion: During ILP, NfL and tau levels increased significantly. No obvious correlations were observed between biomarker release and regional toxicity or decreased muscle strength or sensitivity, although large-scale studies are warranted.
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21.
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22.
  • Gunnarsson, Martin, et al. (author)
  • Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab.
  • 2011
  • In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 69:1, s. 83-9
  • Journal article (peer-reviewed)abstract
    • The impact of present disease-modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain-specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.
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23.
  • Hafsteinsdottir, Brynhildur, 1986, et al. (author)
  • Decreased incidence of Guillain-Barre syndrome during the COVID-19 pandemic: a retrospective population-based study
  • 2023
  • In: Neuroepidemiology. - : S. Karger AG. - 0251-5350 .- 1423-0208. ; 57:1, s. 1-6
  • Journal article (peer-reviewed)abstract
    • Background: Guillain-Barre syndrome is an immune-mediated acute inflammatory polyneuropathy that is associated with various triggers, including certain infections and vaccines. It has been suggested that both SARS-CoV2 infection and vaccination may be triggering factors for Guillain-Barre syndrome, but evidence remain equivocal. Here we conducted a population-based incidence study of Guillain-Barre syndrome spanning the three years immediately prior to and the two years during the pandemic. Methods: Cases were identified by searching a regional diagnostic database for the ICD-10 code for Guillain-Barre syndrome. Individuals who fulfilled the Brighton Criteria for Guillain-Barre syndrome were included. Information on clinical presentation, laboratory values, and vaccination status were retrieved from medical records. We calculated the incidence immediately prior to and during the pandemic.Results: The Guillain-Barre syndrome incidence rate was 1.35/100,000 person-years for the pre-pandemic period, and 0.66/100,000 person-years for the pandemic period (incidence rate ratio: 0.49; p = 0.003). Three cases were temporally associated with SARS-CoV2 infection, and one case each to the Astra Zeneca and Pfizer-BioTech COVID-19 vaccines.Conclusions: Our results show that the incidence of Guillain-Barre syndrome decreased during the pandemic. This is most likely due to decreased prevalence of triggering infections, due to social restrictions. Our findings do not support a causal relationship between Guillain-Barre syndrome and COVID-19.
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24.
  • Hjæresen, Simone, et al. (author)
  • High temperature requirement A1 and macrophage migration inhibitory factor in the cerebrospinal fluid; a potential marker of conversion from relapsing-remitting to secondary progressive multiple sclerosis
  • 2024
  • In: Journal of the Neurological Sciences. - 0022-510X .- 1878-5883. ; 457
  • Journal article (peer-reviewed)abstract
    • Background: Predictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS). Objective: This study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients. Methods: The MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses. Results: The ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity. Conclusion: The HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion.
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25.
  • Hjaeresen, S., et al. (author)
  • MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis
  • 2022
  • In: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X. ; 439
  • Journal article (peer-reviewed)abstract
    • Background: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). Objectives: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. Methods: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. Results: MIF was significantly decreased in treatmentnaive CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly higher in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. Conclusion: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.
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26.
  • Hjaeresen, S., et al. (author)
  • The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis
  • 2021
  • In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 268, s. 3316-3324
  • Journal article (peer-reviewed)abstract
    • Background High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. Objective Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. Methods Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. Results HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. Conclusion HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
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27.
  • Huang, J., et al. (author)
  • Inflammation-related plasma and CSF biomarkers for multiple sclerosis
  • 2020
  • In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:23, s. 12952-12960
  • Journal article (peer-reviewed)abstract
    • Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measur-able in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy sim-ilar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in compari-son to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was asso-ciated with disease duration particularly in patients who had sec-ondary progressive disease (P-CSF < 4 x 10(-5) , P plasma < 4 x 10-5 ), and plasma CCL20 was associated with disease severity (P = 4 x 10(-5) ), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular impor-tance is the set of markers discovered in blood, where validated biomarkers are lacking.
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28.
  • Jernås, Margareta, 1961, et al. (author)
  • MicroRNA regulate immune pathways in T-cells in multiple sclerosis (MS)
  • 2013
  • In: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 14:32
  • Journal article (peer-reviewed)abstract
    • Background: MicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.Methods: Heparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells. MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).Results: We identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls. By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS. The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.Conclusion: These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
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29.
  • Jernås, Margareta, 1961, et al. (author)
  • MS risk genes are transcriptionally regulated in CSF leukocytes at relapse
  • 2013
  • In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:4, s. 403-410
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Infiltrating T-helper cells, cytotoxic T-cells, B-cells and monocytes are thought to mediate the damage to myelin, oligodendrocytes and axons in multiple sclerosis (MS), which results in progressive disability. OBJECTIVE: The objective of this paper is to explore gene expression profiles of leukocytes in the cerebrospinal fluid (CSF) compartment of MS patients during relapse. METHODS: Global gene expression was analyzed by DNA microarray analysis of cells in CSF from MS patients and controls, and verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Fifty percent of the recently described risk genes for MS and 28% of non-risk genes were differently expressed in MS patients compared to controls (χ(2)-test, p=7.7 × 10(-5)). Genes involved in T- and NK-cell processes were up-regulated, and genes involved in processes targeting innate immunity or B-cells were down-regulated in MS. Increased expression of EDN1 and CXCL11 and decreased expression of HMOX1 was verified with real-time PCR and increased expression of CXCL13 was verified with ELISA in CSF. CONCLUSION: DNA microarray analysis is useful in identifying differently expressed genes in CSF leukocytes, which may be important in MS in vivo. Our findings suggest that many of the risk genes for MS are differently expressed in the disease-mediating leukocytes that penetrate the blood-brain barrier.
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30.
  • Johansson, Kalle, et al. (author)
  • Cerebrospinal fluid amyloid precursor protein as a potential biomarker of fatigue in multiple sclerosis: A pilot study
  • 2022
  • In: Multiple Sclerosis and Related Disorders. - : Elsevier BV. - 2211-0348. ; 63
  • Journal article (peer-reviewed)abstract
    • Background: Fatigue is the major cause of disability in MS. Fatigue has been suggested to be primary, part of the neurological disease; it can also be secondary to other diseases outside the CNS or exist as a separate comorbidity. The only forms of measurement currently available are through subjective standardized questionnaires, which are not able to identify primary MS-related fatigue. Therefore, there is a need for objective biomarkers of fatigue in MS. This study explored the viability of 17 possible biomarkers of primary fatigue in MS. Our chosen biomarker panel represents the function and health of different parts of the CNS. Methods: We evaluated 31 MS patients and 17 healthy controls using the Fatigue Severity Scale (FSS) and Insomnia Severity Index (ISI). We assessed clinical parameters and collected CSF from all participants to analyze 17 biomarkers, some of which in multiple targeted sequences, reflecting structural and functional changes in the brain. Based on FSS scores, MS was divided into MS-Fatigue (MS-F, FSS >= 4) and MS-NoFatigue (MS-NoF, FSS < 4). Results: MS-F had significantly lower levels of amyloid precursor protein (APP) peptides than MS-NoF (p = 0.005, p = 0.011). The only biomarker correlating with FSS in any group was APP in MS (r = -0.47, -0.52; p = 0.007, 0.002). APP did not correlate with any clinical parameter in MS but correlated with multiple markers. In MS, FSS correlated with the ISI and months since diagnosis. Conclusion: Although the mechanisms remain unknown, altered APP metabolism in MS seems to be associated with fatigue. APP should be evaluated as a biomarker of the role of structural MS pathology in the development of fatigue in individual MS patients.
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31.
  • Johansson, Kalle, et al. (author)
  • Fatigue, insomnia and daytime sleepiness in multiple sclerosis versus narcolepsy
  • 2021
  • In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 144:5, s. 566-575
  • Journal article (peer-reviewed)abstract
    • Objectives In multiple sclerosis (MS), fatigue is the most prevalent cause of impaired ability to work. In narcolepsy, daytime sleepiness is the main symptom but some studies indicate fatigue being present. We aimed to assess fatigue and associated features in patients with MS or narcolepsy and healthy controls and to assess whether clinical parameters separate fatigued (MS-F) and non-fatigued MS patients (MS-NoF). Materials & Methods In this non-interventional cross-sectional study, we recruited 34 MS patients, 15 narcolepsy type 1 patients and 17 healthy controls. An interviewer administered the Fatigue Severity Scale (FSS), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale, the Patient Health Questionnaire-9 and the Saltin-Grimby Physical Activity Level Scale. Information about clinical parameters and current treatments was collected. Results In its fatigue profile, MS-F resembled the narcolepsy group rather than MS-NoF, which resembled the healthy control group. ISI alone was significantly associated with FSS, and only in MS-NoF and healthy controls; in MS-F and the narcolepsy group, no variable was associated with FSS. Months since diagnosis was the only clinical variable significantly separating MS-F from MS-NoF. In MS, disease duration correlated with fatigue. No clinical variables correlated with fatigue in the narcolepsy group. Conclusions Fatigued MS patients resemble narcolepsy patients more than they resemble non-fatigued MS patients, who resemble healthy controls. Insomnia is the main factor associated with fatigue in MS, while disease duration is the only clinical variable separating fatigued and non-fatigued MS patients. In fatigued patients, variance in fatigue cannot be explained by insomnia, daytime sleepiness, depression or level of exercise.
  •  
32.
  • Johnsson, Magnus, 1983, et al. (author)
  • No increase of serum neurofilament light in relapsing-remitting multiple sclerosis patients switching from standard to extended-interval dosing of natalizumab
  • 2022
  • In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 28:13
  • Journal article (peer-reviewed)abstract
    • Background: Accumulating evidence supports the efficacy of administering natalizumab (NZ) with extended-interval dosing (EID) in patients with relapsing-remitting multiple sclerosis (RRMS). Objectives: We switched NZ dosing from 4-week to 6-week intervals in patients with RRMS, and investigated the effect on serum neurofilament light chain (sNfL) concentrations. Methods: We included two cohorts of patients with RRMS treated with NZ: one received the standard-interval dosing (4 weeks) at baseline, and were switched to 6-week intervals (EID4-6, N = 45). The other cohort received EID (5- or 6-week intervals) both at baseline and during follow-up (EID5/6, N = 25). Serum samples were collected in the EID4-6 cohort at every NZ infusion, for 12 months. The primary outcome was the change in sNfL concentrations after switching to EID. Results: The baseline mean sNfL concentration in the EID4-6 cohort was 10.5 ng/L (standard deviation (SD) = 6.1), and it remained unchanged at 12 months. Moreover, individual sNfL concentrations did not change significantly after extending the NZ dosing intervals. In addition, the EID4-6 and EID5/6 cohorts had similar baseline sNfL concentrations. Conclusion: We concluded that extending the NZ dosing interval did not increase axonal damage, as determined with sNfL, in patients with RRMS.
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33.
  • Johnsson, Magnus, 1983, et al. (author)
  • SARS-COV-2 a trigger of myelin oligodendrocyte glycoprotein-associated disorder
  • 2022
  • In: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 9:8, s. 1296-1301
  • Journal article (peer-reviewed)abstract
    • SARS-COV-2 frequently cause neurological disorders and is sometimes associated with onset of autoimmune diseases affecting the nervous system. Over recent years, a rare but distinct diagnosis designated myelin oligodendrocyte glycoprotein-associated disorder (MOGAD) has been recognized in patients with attacks of optic neuritis, myelitis, or encephalomyelitis and increased levels of anti-MOG antibodies. The cause of MOGAD is unknown. However, there have been reports of single cases of MOGAD in patients with Covid-19 infection. We report a series of SARS-CoV-2 positive patients that developed MOGAD, but a homology search did not support a cross-reactive immune response to SARS-CoV-2 spike-protein and MOG.
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34.
  • Johnsson, Magnus, 1983, et al. (author)
  • Serum neurofilament light for detecting disease activity in individual patients in multiple sclerosis: A 48-week prospective single-center study
  • 2024
  • In: MULTIPLE SCLEROSIS JOURNAL. - 1352-4585 .- 1477-0970.
  • Journal article (peer-reviewed)abstract
    • Background: Serum neurofilament light (sNfL) reflects neuroaxonal damage and is now used as an outcome in treatment trials of relapsing-remitting multiple sclerosis (RRMS). However, the diagnostic properties of sNfL for monitoring disease activity in individual patients warrant further investigations. Method: Patients with suspected relapse and/or contrast-enhancing lesions (CELs) were consecutively included and performed magnetic resonance imaging (MRI) of the brain at baseline and weeks 28 and 48. Serum was obtained at baseline and 2, 4, 8, 16, 24, and 48 weeks. Neurofilament light concentration was measured using Single molecule array technology. Results: We included 44 patients, 40 with RRMS and 4 with clinically isolated syndrome. The median sNfL level peaked at 2 weeks post-baseline (14.6 ng/L, interquartile range (IQR); 9.3-31.6) and reached nadir at 48 weeks (9.1 ng/L, IQR; 5.5-15.0), equivalent to the median sNfL of controls (9.1 ng/L, IQR; 7.4-12). A baseline Z-score of more than 1.1 (area under the curve; 0.78, p < 0.0001) had a sensitivity of 81% and specificity of 70% to detect disease activity. Conclusion: One out of five patients with relapse and/or CELs did not change significantly in post-baseline sNfL levels. The utility of repeated sNfL measurements to monitor disease activity is complementary rather than a substitute for clinical and MRI measures.
  •  
35.
  • Jons, Daniel, 1974, et al. (author)
  • Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis
  • 2021
  • In: Multiple Sclerosis and Related Disorders. - : Elsevier BV. - 2211-0348 .- 2211-0356. ; 56
  • Journal article (peer-reviewed)abstract
    • Background: : A two- to three-fold increase in the risk of multiple sclerosis (MS) after infectious mononucleosis (IM) has been observed in cohort and case control studies. However, this association has not been investigated prospectively from IM. It remains to be determined whether long-term immunospecific sequelae with features consistent with presymptomatic MS occur after IM. Methods: : Sera were obtained from individuals with acute IM from 2003-2007 (n = 42) and from the same individuals at a follow-up (FU) study approximately 10 years after IM. These were assayed for antibodies against a variety of Epstein-Barr virus (EBV) antigens, including gp350, a novel recombinant glycoprotein from the EBV envelope. Similarly, single-protein antigens were used to assess measles and varicella-zoster reactivity (Ncore and varicella-zoster glycoprotein E [VZVgE]). The FU study also included cerebrospinal fluid (CSF) samples from 21 of these individuals to test for IgG antibodies against the same viral antigens. As controls, CSF and serum samples were obtained from 15 EBV-seropositive volunteers who denied a history of IM, and serum samples were obtained from 24 EBV-seropositive blood donors. Anti-gp350, anti-Ncore and anti-VZVgE IgG levels were also analysed in sera and CSF samples from 22 persons with MS. Results: : The FU assays showed higher anti-gp350 IgG (p = 0.007, univariate) than among healthy controls, with no difference in serum anti-VCA or anti-EBNA1 IgG levels and no difference in anti-gp350 in the CSF samples. Anti-Ncore IgG and anti-VZVgE were higher in acute IM samples (p < 0.001 and p < 0.0001, respectively) than at FU, although anti-Ncore remained heightened in an age-adjusted analysis at FU (p = 0.014) compared to the control group. In the MS group, the serum anti-gp350 and anti-Ncore IgG levels were significantly higher than among the control group, but the anti-VZVgE levels were not. The CSF anti-gp350 and VZVgE levels were slightly higher among persons with MS than among the control group, whereas anti-Ncore IgG was markedly higher in persons with MS than in the control group. Conclusion: : In the present study IM showed certain similarities with MS. Increased anti-gp350 reactivity persisted more than a decade after IM, reminiscent of the established increased anti-EBV reactivity in presymptomatic MS. Acute IM was associated with increased anti-measles and anti-VZV immunoreactivity, similar to the MRZ reaction in MS, with some evidence suggesting that this measles reactivity persisted after a decade.
  •  
36.
  • Jons, Daniel, 1974, et al. (author)
  • Intrathecal immunoreactivity in people with or without previous infectious mononucleosis
  • 2020
  • In: Acta Neurologica Scandinavica. - : John Wiley & Sons. - 0001-6314 .- 1600-0404. ; 142:2, s. 161-168
  • Journal article (peer-reviewed)abstract
    • Objectives: The risk of developing multiple sclerosis (MS) increases (OR: 3.1) after infectious mononucleosis (IM). However, the nature of this link is obscure. We tested the hypothesis that IM might incur long-term sequelae, including low-key inflammatory activity, with characteristics of an MS endophenotype (or presymptomatic trait) and that assays of MS-relevant cyto-/chemokines in the cerebrospinal fluid (CSF) post-IM may show a trend in this direction.Materials and methods: We selected seven CSF cytokines (IL-1b, IL-6, YKL-40, TNF-alpha) or chemokines (IL-8, CCL2, IP-10), representing pro-inflammatory factors previously associated with MS. We assayed the CSF levels of these seven cyto-/chemokines in healthy individuals with a median follow-up time of 10 years after serologically confirmed IM (post-IM group, n = 22), and in healthy controls without a history of IM (n = 19). A group of MS patients (n = 23) were included as reference.Results: The CSF levels of IP-10, YKL-40, and CCL-2 were higher in the post-IM group than in our IM unexposed controls (P = .021, .049, .028). Seven of seven cyto-/chemokine assays showed a trend in the predicted direction (Pof binomial ratio = .008). However, this trend was non-significant in a multivariate test (P = .22). A power analysis indicated that similar studies including a larger cohort would be numerically realistic.Conclusions: These results do not reject the hypothesis that the established epidemiological association between IM and MS results from a stepwise inflammatory propagation from IM sequelae to an MS endophenotype (or presymptomatic trait) in a proportion of IM patients, pending confirmation with adequate power.
  •  
37.
  • Kuhle, J, et al. (author)
  • Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis
  • 2013
  • In: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 128:6
  • Journal article (peer-reviewed)abstract
    • Neurofilaments are promising biomarkers in multiple sclerosis (MS) and increased levels in cerebrospinal fluid (CSF) indicate axonal damage or degeneration. In a previous study, neurofilament light chain (NfL) levels in CSF of relapsing remitting (RR) patients with MS were normalized by natalizumab treatment.We compared the coherence between NfL and neurofilament heavy chain (NfH(SMI) (35) ) levels in longitudinal CSF samples in a subset of these patients.In 30 patients with RRMS, CSF was obtained prior to and following 12months of natalizumab treatment. NfH(SMI) (35) was measured by an electrochemiluminescence-based immunoassay. NfL levels were determined previously by the UmanDiagnostics NF-light(®) assay.NfH(SMI) (35) decreased in 73.3% and NfL in 90% of the patients following natalizumab treatment (32.4 vs 27.4pg/ml, P=0.002 and 820 vs 375pg/ml, P<0.0001). Patients experiencing a relapse showed higher NfH(SMI) (35) levels compared with patients in remission (47.7 vs 27.6pg/ml, n=8, P=0.001). This difference was less obvious for NfL (1055 vs 725pg/ml, P=0.256). In patients in remission, NfL levels were lower following natalizumab treatment (830 vs 365pg/ml, n=20, P=0.0002), whereas the same comparison failed significance for NfH(SMI) (35) (28.3 vs 26.9pg/ml, P=0.086).We confirm previous findings, indicating reduced axonal damage under natalizumab treatment by measuring NfH(SMI) (35) , using an assay with independent methodology. In comparison with NfH(SMI) (35) , NfL changes were more pronounced and the treatment effect also included patients in remission. Our results suggest that NfL is superior over NfH(SMI) (35) as therapeutic biomarker and is a promising candidate to measure neuroaxonal damage in MS treatment trials.
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38.
  • Malmeström, Clas, 1965, et al. (author)
  • CSF levels of YKL-40 are increased in MS and replaces with immunosuppressive treatment.
  • 2014
  • In: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 269:1-2, s. 87-9
  • Journal article (peer-reviewed)abstract
    • The role of glial cells during different phases of multiple sclerosis (MS) is unclear. To monitor glial activation we analyzed the biomarkers YKL-40 and sCD14 in cerebrospinal fluid (CSF) from MS patients during different disease phases and in response to immunosuppressive treatment. CSF levels of YKL-40 were increased in MS during relapse, remission and secondary progression compared with healthy controls. Furthermore, YKL-40 levels in CSF decreased by mitoxantrone and natalizumab treatment. No differences were observed in CSF levels of sCD14. Thus, we can infer that glial activation is present in all MS phases and decreases by immunosuppressive treatment.
  •  
39.
  • Malmeström, Clas, 1965, et al. (author)
  • Serum levels of LIGHT in MS
  • 2013
  • In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:7, s. 871-876
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Recently, a polymorphism in the LIGHT gene was shown to increase the risk of multiple sclerosis (MS) in a genome-wide association study (GWAS). OBJECTIVE: Our aim was to investigate if serum levels of LIGHT were affected by this polymorphism and by the disease itself. METHODS: Serum levels of LIGHT were investigated in four cohorts; 1) MS (n = 159) and controls (n = 160) in relation to rs1077667 genotype; 2) MS at relapse (n = 30) vs. healthy controls (n = 26); 3) MS (n = 27) vs. other neurological disease (OND, n = 33); and 4) MS patients before and after one year of treatment with natalizumab (n = 30). RESULTS: Carriers of the GG genotype had the lowest serum levels of LIGHT (p=0.02). Serum levels of LIGHT were increased in MS at relapse in two separate cohorts: vs. healthy controls (p=0.00005) and vs. remission (p=0.00006), other neurological disease (OND) (p=0.002) and OND with signs of inflammation (iOND; p=0.00005). Furthermore, serum levels of LIGHT were decreased by natalizumab treatment (p=0.001). CONCLUSION: Soluble LIGHT is an inhibitor of T-cell activation and GG carriers of rs1077667, with the highest risk for MS, had the lowest serum levels. The increased levels of LIGHT at times of increased MS activity suggest that soluble LIGHT is protective and may act to limit inflammation.
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40.
  •  
41.
  • Novakova, Lenka, 1984, et al. (author)
  • Medically unexplained symptoms are common in women in tertiary neurological healthcare center: A survey cohort study of persons investigated for suspected multiple sclerosis
  • 2024
  • In: BRAIN AND BEHAVIOR. - 2162-3279. ; 14:3
  • Journal article (peer-reviewed)abstract
    • Background: A significant proportion of individuals with suspicious onset of multiple sclerosis (MS) does not fulfill the diagnostic criteria. Although some receive other diagnoses, many remain undiagnosed and lack healthcare follow-up. This study aimed to characterize persons with undetermined diagnosis (PwUD) through a questionnaire. Methods: Incident cases with suspected MS were consecutively admitted to a tertiary neurological healthcare center in a prospective cohort study. Those who remained undiagnosed after 40 months (mean, range 31-52) were considered PwUD. They completed a modified questionnaire, previously used in a population-based case-control study of incident MS cases. Their responses were compared with two control cohorts, persons with MS (PwMS) and healthy controls, randomly selected from national registries, matched by age, gender, and area of residence. Results: Out of 271 patients with suspected MS onset, 72 (20.3%) were PwUD with a female majority (79%). The response rate was 83% and 39% reported persisting MS-like symptoms. Compared to controls (n = 548) and PwMS (n = 277), fewer PwUD were currently smoking (p = .4 and p = .03), consumed less alcohol (p = .04 and p = .01), and had children (p = .02 and p = .002). PwUD reported occurrence of other autoimmune disease in 29%, higher compared to PwMS and controls (p < .001 and p < .001). Conclusions: UD is common among persons investigated for suspected MS, in particular among female parents. Our data suggest that PwUD can be characterized as nonsmokers with low alcohol consumption and a higher prevalence of autoimmune disease, in particular thyroid disease.
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42.
  • Novakova, Lenka, 1984, et al. (author)
  • Monitoring disease activity in multiple sclerosis using serum neurofilament light protein.
  • 2017
  • In: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X .- 0028-3878. ; 89:22, s. 2230-2237
  • Journal article (peer-reviewed)abstract
    • To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.
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43.
  • Novakova, Lenka, 1984, et al. (author)
  • Reduced cerebrospinal fluid concentrations of oxysterols in response to natalizumab treatment of relapsing remitting multiple sclerosis.
  • 2015
  • In: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X .- 1878-5883. ; 358:1-2, s. 201-206
  • Journal article (peer-reviewed)abstract
    • Abstract 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.
  •  
44.
  • Novakova, Lenka, et al. (author)
  • Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers
  • 2018
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 13:4
  • Journal article (peer-reviewed)abstract
    • Background Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization. Objective This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course. Methods This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: Patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: Cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction. Results Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration. Conclusions In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.
  •  
45.
  • Nováková Nyrén, Lenka, et al. (author)
  • Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis.
  • 2017
  • In: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 141:2, s. 296-304
  • Journal article (peer-reviewed)abstract
    • Cerebrospinal fluid (CSF) biomarkers can reflect different aspects of the pathophysiology of relapsing-remitting multiple sclerosis (RRMS). Understanding the impact of different disease modifying therapies on the CSF biomarker profile may increase their implementation in clinical practice and their appropriateness for monitoring treatment efficacy. This study investigated the influence of first-line (interferon beta) and second-line (natalizumab) therapies on seven CSF biomarkers in RRMS and their correlation with clinical and radiological outcomes. We included 59 RRMS patients and 39 healthy controls. The concentrations of C-X-C motif chemokine 13 (CXCL13), C-C motif chemokine ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein, neurofilament light protein (NFL), and neurogranin were determined by ELISA, and chitotriosidase (CHIT1) was analyzed by spectrofluorometry. RRMS patients had higher levels of NFL, CXCL13, CHI3L1, and CHIT1 than controls (p<0.001). Subgroup analysis revealed higher NFL, CXCL13 and CHIT1 levels in patients treated with first-line therapy compared to second-line therapy (p=0.008, p=0.001 and p=0.026, respectively). NFL and CHIT1 levels correlated with relapse status, and NFL and CXCL13 levels correlated with the formation of new magnetic resonance imaging lesions. Furthermore, we found an association between inflammatory and degenerative biomarkers. The results indicate that CSF levels of NFL, CXCL13, CHI3L1, and CHIT1 correlate with the clinical and/or radiological disease activity, providing additional dimensions in the assessment of treatment efficacy.
  •  
46.
  • Rabenstein, M., et al. (author)
  • The impact of hybrid immunity on immune responses after SARS-CoV-2 vaccination in persons with multiple sclerosis treated with disease-modifying therapies
  • 2023
  • In: European Journal of Neurology. - 1351-5101 .- 1468-1331. ; 30:12, s. 3789-3798
  • Journal article (peer-reviewed)abstract
    • Background and purpose: Hybrid immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develops from a combination of natural infection and vaccine-generated immunity. Multiple sclerosis (MS) disease-modifying therapies (DMTs) have the potential to impact humoral and cellular immunity induced by SARS-CoV-2 vaccination and infection. The aims were to compare antibody and T-cell responses after SARS-CoV-2 mRNA vaccination in persons with MS (pwMS) treated with different DMTs and to assess differences between naively vaccinated pwMS and pwMS with hybrid immunity vaccinated following a previous SARS-CoV-2 infection.Methods: Antibody and T-cell responses were determined in pwMS at baseline and 4 and 12 weeks after the second dose of SARS-CoV-2 vaccination in 143 pwMS with or without previous SARS-CoV-2 infection and 40 healthy controls (HCs). The MS cohort comprised natalizumab (n = 22), dimethylfumarate (n = 23), fingolimod (n = 38), cladribine (n = 30), alemtuzumab (n = 17) and teriflunomide (n = 13) treated pwMS. Immunoglobulin G antibody responses to SARS-CoV-2 antigens were measured using a multiplex bead assay and FluoroSpot was used to assess T-cell responses (interferon gamma and interleukin 13).Results: Humoral and T-cell responses to vaccination were comparable between naively vaccinated HCs and pwMS treated with natalizumab, dimethylfumarate, cladribine, alemtuzumab and teriflunomide, but were suppressed in fingolimod-treated pwMS. Both fingolimod-treated pwMS and HCs vaccinated following a previous SARS-CoV-2 infection had higher antibody levels 4 weeks after vaccination compared to naively vaccinated individuals. Antibody and interferon gamma levels 12 weeks after vaccination were positively correlated with time from last treatment course of cladribine.Conclusion: These findings are of relevance for infection risk mitigation and for vaccination strategies amongst pwMS undergoing DMT.
  •  
47.
  • Rosenstein, Igal, 1984, et al. (author)
  • Association of serum glial fibrillary acidic protein with progression independent of relapse activity in multiple sclerosis.
  • 2024
  • In: Journal of neurology. - 1432-1459.
  • Journal article (peer-reviewed)abstract
    • Insidious disability worsening is a common feature in relapsing-remitting multiple sclerosis (RRMS). Many patients experience progression independent of relapse activity (PIRA) despite being treated with high efficacy disease-modifying therapies. We prospectively investigated associations of body-fluid and imaging biomarkers with PIRA.Patients with early RRMS (n=104) were prospectively included and followed up for 60months. All patients were newly diagnosed and previously untreated. PIRA was defined using a composite score including the expanded disability status scale, 9-hole peg test, timed 25 foot walk test, and the symbol digit modalities test. Eleven body fluid and imaging biomarkers were determined at baseline and levels of serum neurofilament light (sNfL) and glial fibrillary acidic protein (sGFAP) were also measured annually thereafter. Association of baseline biomarkers with PIRA was investigated in multivariable logistic regression models adjusting for clinical and demographic confounding factors. Longitudinal serum biomarker dynamics were investigated in mixed effects models.Only sGFAP was significantly higher in PIRA at baseline (median [IQR] 73.9 [60.9-110.1] vs. 60.3 [45.2-79.9], p=0.01). A cut-off of sGFAP>65 pg/mL resulted in a sensitivity of 68% and specificity of 61%, to detect patients at higher risk of PIRA. In a multivariable logistic regression, sGFAP>65 pg/mL was associated with higher odds of developing PIRA (odds ratio 4.3, 95% CI 1.44-12.86, p=0.009). Repeated measures of sGFAP levels showed that patients with PIRA during follow-up had higher levels of sGFAP along the whole follow-up compared to stable patients (p<0.001).Determination of sGFAP at baseline and follow-up may be useful in capturing disability accrual independent of relapse activity in early RRMS.
  •  
48.
  • Rosenstein, Igal, 1984, et al. (author)
  • Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study
  • 2022
  • In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 28:6
  • Journal article (peer-reviewed)abstract
    • Background: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions. Objective: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS). Methods: RRMS patients (n = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001-2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization. Results: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499-2744] ng/L) than those without relapse (264 [125-537] ng/L, p < 0.001) and patients with gadolinium-enhancing lesions had 3.3 times higher median NFL (1414 [606.8-3210] ng/L) than those without (426 [IQR 221-851] ng/L, p < 0.001). The sensitivity and specificity of cNFL to detect disease activity was 75% and 98.5%, respectively. High cNFL at MS onset predicted progression to Expanded Disability Status Scale (EDSS) > 3 (p < 0.001, hazard ratios (HR) = 1.89, 95% CI = 1.44-2.65) and conversion to secondary progressive MS (SPMS, p = 0.001, HR = 2.5, 95% CI = 1.4-4.2). Conclusions: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset.
  •  
49.
  • Rosenstein, Igal, 1984, et al. (author)
  • High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis
  • 2023
  • In: FRONTIERS IN IMMUNOLOGY. - : Frontiers Media SA. - 1664-3224. ; 14
  • Journal article (peer-reviewed)abstract
    • BackgroundEvolving evidence suggests that measurement of cerebrospinal fluid (CSF) kappa free light chain (KFLC) synthesis has high diagnostic sensitivity and specificity for multiple sclerosis (MS), but its prognostic ability is less investigated. The usefulness of KFLC in predicting cognitive impairment (CI) is still unknown. MethodsIn a monocentric longitudinal retrospecitve cohort study, KFLC-index ([CSF KFLC/serum KFLC]/[CSF albumin/serum albumin]) measured by latex-enhanced immunonephelometry was prospectively determined as part of the diagnostic workup in patients with early relapsing-remitting MS (RRMS, n=77). The ability of KFLC-index to predict information processing speed (IPS) worsening as assessed with the symbol digit modalities test (SDMT) was investigated in univariable and multivariable models. ResultsIn patients with KFLC-index>100 (n=31), 11 subjects (35.5%) showed reduced SDMT scores by >= 8 points at follow-up (mean follow-up time 7.3 +/- 2.6 years), compared with their baseline scores (p=0.01). Baseline KFLC-index>100 was strongly associated with a higher hazard of SDMT score reduction at follow-up (adjusted hazard ratio 10.5, 95% confidence interval 2.2-50.8, p=0.003; median time to SDMT reduction 7 years). ConclusionIntrathecal KFLC synthesis has become an attractive diagnostic tool for MS. We show for the first time that in a real-world setting of early RRMS, KFLC-index predicted cognitive decline. Whether this predictive ability of KFLC-index also concerns other cognitive domains than IPS, warrants further investigations.
  •  
50.
  • Rosenstein, Igal, 1984, et al. (author)
  • Increased intrathecal neurofilament light and immunoglobulin M predict severe disability in relapsing-remitting multiple sclerosis
  • 2022
  • In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
  • Journal article (peer-reviewed)abstract
    • BackgroundEmerging evidence supports that determination of intrathecal immunoglobulin M (IgM) synthesis (ITMS) and neurofilament light (NfL) concentration in cerebrospinal fluid (CSF) may be clinically useful as disease severity biomarkers in relapsing-remitting multiple sclerosis (RRMS). MethodsMonocentric observational longitudinal cohort study in which prospectively collected data were retrospectively retrieved. Included were patients with RRMS (n=457) who had a diagnostic investigation including analysis of ITMS and CSF neurofilament light (cNfL). ITMS was calculated with the linear index formula, the intrathecal fraction of IgM according to Reiber (IgM(IF)), and by qualitative determination of oligoclonal IgM bands (OCMB). Univariable and multivariable models were performed to predict Evidence of Disease Activity-3 (EDA-3) status within 24 months from onset, and the risk of Expanded Disability Status Score (EDSS) >= 3 and >= 6. ResultsAll investigated methods to calculate ITMS significantly predicted evidence of disease activity (EDA-3) within 24 months. IgM(IF)>0% showed the strongest association with EDA-3 status (adjusted hazard ratio [aHR] 3.7, 95%CI 2.7-5, p<0.001). Combining IgM-index>0.1 or OCMB with increased cNfL were strong predictors of EDSS >= 3 (for cNfL(+)/IgM-index(+): aHR 4.6, 95%CI 2.6-8.2, p<0.001) and EDSS >= 6 (aHR 8.2, 95%CI 2.3-30, p<0.001). ConclusionsIn a real-world setting, ITMS was a useful biomarker in early RRMS to predict disabling MS and its prognostic value was even stronger in combination with cNfL. Our data suggest that determination of ITMS and cNfL should be included in the diagnostic work-up of RRMS for prognostic purposes and in decisions of disease-modifying therapy.
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