| 1. |
- Lundblad, Linda, et al.
(author)
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Processing in prefrontal cortex underlies tactile direction discrimination: An fMRI study of a patient with a traumatic spinal cord lesion.
- 2010
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In: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 483:3, s. 197-200
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Journal article (peer-reviewed)abstract
- We have investigated cortical processing of tactile direction discrimination (TDD) in a patient with unilateral tactile disturbance due to spinal cord lesion. The patient R.A. (male, 45 years old), suffers from a traumatic dorsal column lesion at the level of Th XI-XII on the right side. He was instructed to report the direction of 2mm long skin pull stimulations applied in a proximal or distal direction on his right or left lower legs during functional magnetic resonance imaging (fMRI). Although R.A. considered himself to have nearly normal tactile sensibility, testing showed severely disturbed TDD on his right leg whereas results were within the range of healthy subjects on his left leg. For both legs TDD activated an extensive cortical network that included opercular parietal area 1 (OP1) of the second somatosensory cortex (S2), as has previously been observed in healthy subjects. However, dorsolateral prefrontal cortex (DLPFC) and anterior insular cortex (AIC) were only activated for the unaffected (left) leg where TDD was normal. A revisit of previously published data showed that healthy subjects consistently had TDD-related activations in DLPFC and AIC. However, in several healthy subjects AIC, but not DLPFC, was also activated for skin pull stimulations per se without the TDD task. Thus, the patient's data, in conjunction with the previous results from healthy subjects, suggest that DLPFC processing is important for tactile decision making based on proper tactile input.
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| 2. |
- O'Connor, Laura, et al.
(author)
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Pregnancy outcomes for women with myasthenia gravis and their newborns: A nationwide register-based cohort study
- 2023
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In: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 31:1
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Journal article (peer-reviewed)abstract
- Background and Purpose: Few large-scale studies examine whether maternal myasthenia gravis (MG) is a risk factor for complications during pregnancy and childbirth. This study evaluated whether maternal MG is associated with an increased risk of adverse pregnancy, delivery, and neonatal outcomes.Methods: We conducted a nationwide Swedish register-based cohort study of women who gave birth to singleton infants (>= 22 gestational weeks) during 1987-2019. Exposed women were diagnosed with MG before or during the index pregnancy (N = 443). Unexposed women comprised 4249 women without a diagnosis of MG, matched for age, parity, hospital, and year of childbirth. The risks of adverse pregnancy, delivery, and neonatal outcomes for women with MG were estimated using regression modeling and presented as adjusted odds ratios (aOR).Results :There was no increased risk of pregnancy complications in women with MG. Women with MG had a spontaneous onset of labor less often than women without MG (69.8% vs. 79.5%; aOR 0.59; p < 0.001) as well as higher labor induction rates and elective cesarean section deliveries (16.0% vs. 12.3%, aOR 1.42; p = 0.02 and 12.0% vs. 8.1%, aOR 1.59; p = 0.009). Infants of women with MG were born on average 2 days earlier (p = 0.002); however, these infants did not have a higher risk of having low APGAR, being small for gestational age, or having a congenital malformation.Conclusion :This first nationwide study of pregnancy in women with MG in Sweden demonstrates reassuring results overall, suggesting generally safe pregnancy outcomes for women with MG and their infants.
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| 3. |
- Alping, P., et al.
(author)
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Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients
- 2016
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:6, s. 950-958
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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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| 4. |
- Augutis, Kristin, et al.
(author)
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Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis.
- 2013
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:5, s. 543-52
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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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| 5. |
- Axelsson, Markus, 1975, et al.
(author)
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Cerebrospinal fluid NCAM levels are modulated by disease-modifying therapies
- 2019
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In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 139:5, s. 411-427
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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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| 6. |
- Axelsson, M, et al.
(author)
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Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis.
- 2011
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In: Journal of neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 258:5, s. 882-8
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Journal article (peer-reviewed)abstract
- The major intermediate cytoskeletal protein of astrocytes, glial fibrillary acidic protein (GFAP), and that of axons, neurofilament light protein (NFL), may both be released into the cerebrospinal fluid (CSF) during pathological processes in the central nervous system (CNS). We investigated GFAP and NFL levels in CSF as possible biomarkers for progression in multiple sclerosis (MS). Patients with relapsing-remitting MS (RRMS, n = 15) or secondary progressive MS (SPMS, n = 10) and healthy control subjects (n = 28) were examined twice with an interval of 8-10 years apart. Neurological deficits were scored with the Expanded Disability Status Scale (EDSS). GFAP and NFL levels were determined in CSF by enzyme-linked immunosorbent assay (ELISA). GFAP levels and NFL levels correlated with age (r and r (s) = 0.50, p = 0.006). Adjusting for age, MS patients had increased GFAP levels compared with controls (p = 0.03) and GFAP levels correlated with neurological disability (EDSS, r = 0.51, p < 0.05) and disease progression [Multiple Sclerosis Severity Score (MSSS), r = 0.47, p < 0.05]. The mean annual increase of GFAP was 6.5 ng/L for controls, 8.1 ng/L for RRMS patients, and 18.9 ng/L for SPMS patients. GFAP level at the first examination had predictive value for neurological disability 8-10 years later (EDSS, r = 0.45, p < 0.05) but not for EDSS increase between the examinations. NFL levels were not significantly increased in MS patients compared with controls and had no relationship to disability or progression and no prognostic value for disability development. GFAP, a marker for astrogliosis, is a potential biomarker for MS progression and may have a role in clinical trials for assessing the impact of therapies on MS progression.
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| 7. |
- Axelsson, Markus, 1975, et al.
(author)
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Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis.
- 2014
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - London, United Kingdom : SAGE Publications. - 1477-0970 .- 1352-4585. ; 20:1, s. 43-50
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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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| 8. |
- Axelsson, Markus, 1975, et al.
(author)
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The influence of disease duration, clinical course, and immunosuppressive therapy on the synthesis of intrathecal oligoclonal IgG bands in multiple sclerosis.
- 2013
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In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728. ; 264:1-2, s. 100-5
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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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| 9. |
- Burman, Joachim, et al.
(author)
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YKL-40 is a CSF biomarker of intrathecal inflammation in secondary progressive multiple sclerosis.
- 2016
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In: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 292, s. 52-7
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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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| 10. |
- Constantinescu, Clara, 1995, et al.
(author)
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Persons with suspicious onset of multiple sclerosis but with undetermined diagnosis had persistent lower cognition and reduced quality of life
- 2021
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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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| 11. |
- Constantinescu, Radu, 1966, et al.
(author)
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Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies.
- 2017
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In: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 306, s. 25-30
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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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| 12. |
- Constantinescu, Radu, 1966, et al.
(author)
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Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis
- 2016
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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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| 13. |
- Gunnarsson, Martin, et al.
(author)
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Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab.
- 2011
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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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| 14. |
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| 15. |
- Huang, J., et al.
(author)
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Inflammation-related plasma and CSF biomarkers for multiple sclerosis
- 2020
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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
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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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| 16. |
- Jernås, Margareta, 1961, et al.
(author)
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MicroRNA regulate immune pathways in T-cells in multiple sclerosis (MS)
- 2013
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In: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 14:32
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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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| 17. |
- Jernås, Margareta, 1961, et al.
(author)
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MS risk genes are transcriptionally regulated in CSF leukocytes at relapse
- 2013
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:4, s. 403-410
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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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| 18. |
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| 19. |
- Johansson, Gustav, et al.
(author)
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Ultrasensitive DNA Immune Repertoire Sequencing Using Unique Molecular Identifiers.
- 2020
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In: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 66:9, s. 1228-1237
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Journal article (peer-reviewed)abstract
- Immune repertoire sequencing of the T-cell receptor can identify clonotypes that have expanded as a result of antigen recognition or hematological malignancies. However, current sequencing protocols display limitations with nonuniform amplification and polymerase-induced errors during sequencing. Here, we developed a sequencing method that overcame these issues and applied it to γδ T cells, a cell type that plays a unique role in immunity, autoimmunity, homeostasis of intestine, skin, adipose tissue, and cancer biology.The ultrasensitive immune repertoire sequencing method used PCR-introduced unique molecular identifiers. We constructed a 32-panel assay that captured the full diversity of the recombined T-cell receptor delta loci in γδ T cells. The protocol was validated on synthetic reference molecules and blood samples of healthy individuals.The 32-panel assay displayed wide dynamic range, high reproducibility, and analytical sensitivity with single-nucleotide resolution. The method corrected for sequencing-depended quantification bias and polymerase-induced errors and could be applied to both enriched and nonenriched cells. Healthy donors displayed oligoclonal expansion of γδ T cells and similar frequencies of clonotypes were detected in both enrichment and nonenriched samples.Ultrasensitive immune repertoire sequencing strategy enables quantification of individual and specific clonotypes in a background that can be applied to clinical as well as basic application areas. Our approach is simple, flexible, and can easily be implemented in any molecular laboratory.
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| 20. |
- Johnsson, Magnus, 1983, et al.
(author)
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No increase of serum neurofilament light in relapsing-remitting multiple sclerosis patients switching from standard to extended-interval dosing of natalizumab
- 2022
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 28:13
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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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| 21. |
- Johnsson, Magnus, 1983, et al.
(author)
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SARS-COV-2 a trigger of myelin oligodendrocyte glycoprotein-associated disorder
- 2022
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In: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 9:8, s. 1296-1301
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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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| 22. |
- Johnsson, Magnus, 1983, et al.
(author)
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Serum neurofilament light for detecting disease activity in individual patients in multiple sclerosis: A 48-week prospective single-center study
- 2024
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In: MULTIPLE SCLEROSIS JOURNAL. - 1352-4585 .- 1477-0970. ; 30:6, s. 664-673
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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.
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| 23. |
- Jons, Daniel, 1974, et al.
(author)
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Intrathecal immunoreactivity in people with or without previous infectious mononucleosis
- 2020
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In: Acta Neurologica Scandinavica. - : John Wiley & Sons. - 0001-6314 .- 1600-0404. ; 142:2, s. 161-168
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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.
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| 24. |
- Kneider, Maria, et al.
(author)
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Upper Respiratory Infections and MRI Activity in Relapsing-Remitting Multiple Sclerosis
- 2015
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In: Neuroepidemiology. - : S. Karger AG. - 0251-5350 .- 1423-0208. ; 45:2, s. 83-89
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Journal article (peer-reviewed)abstract
- Background: Although clinical reports have suggested a relationship between systemic infections and multiple sclerosis (MS) relapses, MRI evidence supporting an association is conflicting. Here we evaluated the temporal relationship between upper respiratory infections (URIs) and MRI activity in relapsing-remitting (RR) MS. Methods: We combined individual data on URI with data on active lesions in pre-scheduled MRI examinations performed every 4 weeks for 28 weeks in 69 patients. A 4-week at-risk (AR) period started, by definition, 1 week before the onset of a URI. We recorded the relationship between the number of active lesions in each MRI with (1) the number of days of AR time in the immediately preceding 4-week period and (2) the number of days passed since the onset of a preceding URI. Results: Average MRI lesions/day showed no difference between AR (0.0764) and not-AR (0.0774) periods. The number of lesions in 483 pre-scheduled MRI examinations did not correlate with the AR proportion in the prior 4-week period (rho = -0.03), and time from URI onset did not correlate with lesion number on the next MRI examination (rho = 0.003). Conclusion: The occurrence of a URI did not increase the risk of MRI activity evaluated in an adjacent 4-week window in RRMS.
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| 25. |
- Kosek, S., et al.
(author)
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Antibody-Positive Autoimmune Encephalitis and Paraneoplastic Neurological Syndrome: Epidemiology and Outcome of Neuronal Antibody Testing in Sweden
- 2023
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In: ACTA NEUROLOGICA SCANDINAVICA. - : WILEY. - 0001-6314 .- 1600-0404. ; 2023
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Journal article (peer-reviewed)abstract
- Objective. To estimate the 5-year incidence rate of autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS) in Sweden. Methods. All patients who were tested for a neuronal antibody in Sweden between 2015 and 2019 were included. Patients in Healthcare region Mid Sweden (population 2.1 million) were invited to participate in a case ascertainment substudy. AE and PNS cases were defined using established diagnostic criteria. Crude and age-adjusted incidence rates of AE and PNS in Healthcare region Mid Sweden were estimated. Results. The number of tests for neuronal antibodies in Sweden increased between 2015 and 2019 from 1867 to 2505 (serum) and 863 to 1376 (CSF) per annum. The frequencies of positive results were stable over the entire study period, and the mean value was 6.1% for serum (CI95% 5.5-6.7) and 4.8% for CSF (CI95% 4.0-5.6). In total, 125 patients tested positive for neuronal antibodies in Healthcare region Mid Sweden between 2015 and 2019. Of these, 94 were included, and after case ascertainment, thirty-one cases of definite AE or PNS could be identified. The 5-year incidence rate of AE and PNS was 3.0 per million person-years (95% CI 1.9-4.1). The yearly incidence rates increased in the study period, from 1.5 per million person-years in 2015 (95% CI 0.0-3.2) to 4.3 per million person-years in 2019 (95% CI 1.5-7.1). Conclusions. In this first epidemiological study of AE and PNS in Sweden, the number of cases doubled from 2015 to 2019. This likely reflects increased availability of testing and awareness of these conditions.
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