Publications by authors named "Fredrik Piehl"

178 Publications

Risk of depression in multiple sclerosis across disease-modifying therapies.

Mult Scler 2021 Jul 15:13524585211031128. Epub 2021 Jul 15.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Depression and use of antidepressants are more common among patients with multiple sclerosis (MS) compared to the general population, but the relation of psychiatric comorbidity to use of different disease-modifying therapies (DMTs) is less clear.

Objective: To determine whether risk of incident depression or antidepressant use differed across DMTs, and to assess whether depression and antidepressants affected risk of DMT discontinuation and MS relapses.

Methods: We prospectively followed for 8 years a register-based nationwide cohort of 3803 relapsing-remitting MS patients.

Results: Patients on rituximab had a lower risk of being diagnosed with depression or initiating antidepressants compared with the reference group treated with interferons (hazard ratio (HR) = 0.72, 95% confidence interval (CI) = 0.54-0.96). Patients diagnosed with depression discontinued interferon treatment to a higher extent than patients without depression (HR = 1.51; 95% CI = 1.15-1.98), as did patients on fingolimod initiating an antidepressant compared to patients who did not initiate an antidepressant (HR = 1.47; 95% CI = 1.04-2.08).

Conclusions: Our results indicate that the choice of DMT is associated with subsequent risk of depression in MS, but further studies are needed to establish whether there is a causal link. Overall, depression and use of antidepressants displayed limited associations with DMT discontinuation and MS relapse.
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http://dx.doi.org/10.1177/13524585211031128DOI Listing
July 2021

Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury.

J Immunol 2021 Jun 18. Epub 2021 Jun 18.

Department of Clinical Neurosciences, University of Cambridge, United Kingdom.

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
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http://dx.doi.org/10.4049/jimmunol.2001309DOI Listing
June 2021

Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, SE-171 76 Stockholm, Sweden;

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). Small non-coding RNAs (sncRNAs) and, in particular, microRNAs (miRNAs) have frequently been associated with MS. Here, we performed a comprehensive analysis of all classes of sncRNAs in matching samples of peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from relapsing-remitting (RRMS, = 12 in relapse and = 11 in remission) patients, secondary progressive (SPMS, = 6) MS patients, and noninflammatory and inflammatory neurological disease controls (NINDC, = 11; INDC, = 5). We show widespread changes in miRNAs and sncRNA-derived fragments of small nuclear, nucleolar, and transfer RNAs. In CSF cells, 133 out of 133 and 115 out of 117 differentially expressed sncRNAs were increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65 out of 67 differentially expressed PBMC sncRNAs were decreased in RRMS compared to NINDC. The striking contrast between the periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation, and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the CNS target organ.
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http://dx.doi.org/10.1073/pnas.2011574118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092379PMC
April 2021

Plasma bilirubin levels are reduced in first-episode psychosis patients and associates to working memory and duration of untreated psychosis.

Sci Rep 2021 Apr 6;11(1):7527. Epub 2021 Apr 6.

Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0-13.0] µM vs. 15.0 [11.5-18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = - 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.
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http://dx.doi.org/10.1038/s41598-021-87096-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024299PMC
April 2021

Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood-brain barrier disruption and outcome prediction following severe traumatic brain injury: a prospective, observational study.

Crit Care 2021 03 12;25(1):103. Epub 2021 Mar 12.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls.

Methods: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (Q), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort.

Results: TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with Q, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR = 7.4%) and complement factor B in serum (p = 0.003, ΔR = 9.2%) were independent outcome predictors also following step-down modelling.

Conclusions: This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.
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http://dx.doi.org/10.1186/s13054-021-03503-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955664PMC
March 2021

Hospital-diagnosed infections before age 20 and risk of a subsequent multiple sclerosis diagnosis.

Brain 2021 Mar 9. Epub 2021 Mar 9.

Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.

The involvement of specific viral and bacterial infections as risk factors for multiple sclerosis has been studied extensively. However, whether this extends to infections in a broader sense is less clear and little is known about whether risk of a multiple sclerosis diagnosis is associated with other types and sites of infections, such as of the CNS. This study aims to assess if hospital-diagnosed infections by type and site before age 20 years are associated with risk of a subsequent multiple sclerosis diagnosis and whether this association is explained entirely by infectious mononucleosis, pneumonia, and CNS infections. Individuals born in Sweden between 1970-1994 were identified using the Swedish Total Population Register (n = 2,422,969). Multiple sclerosis diagnoses from age 20 years and hospital-diagnosed infections before age 20 years were identified using the Swedish National Patient Register. Risk of a multiple sclerosis diagnosis associated with various infections in adolescence (11-19 years) and earlier childhood (birth-10 years) was estimated using Cox regression, with adjustment for sex, parental socioeconomic position, and infection type. None of the infections by age 10 years were associated with risk of a multiple sclerosis diagnosis. Any infection in adolescence increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.33, 95% confidence interval 1.21-1.46) and remained statistically significant after exclusion of infectious mononucleosis, pneumonia, and CNS infection (hazard ratio 1.17, 95% confidence interval 1.06-1.30). CNS infection in adolescence (excluding encephalomyelitis to avoid including acute disseminated encephalitis) increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.85, 95% confidence interval 1.11-3.07). The increased risk of a multiple sclerosis diagnosis associated with viral infection in adolescence was largely explained by infectious mononucleosis. Bacterial infections in adolescence increased risk of a multiple sclerosis diagnosis, but the magnitude of risk reduced after excluding infectious mononucleosis, pneumonia and CNS infection (hazard ratio 1.31, 95% confidence interval 1.13-1.51). Respiratory infection in adolescence also increased risk of a multiple sclerosis diagnosis (hazard ratio 1.51, 95% confidence interval 1.30-1.75), but was not statistically significant after excluding infectious mononucleosis and pneumonia. These findings suggest that a variety of serious infections in adolescence, including novel evidence for CNS infections, are risk factors for a subsequent multiple sclerosis diagnosis, further demonstrating adolescence is a critical period of susceptibility to environmental exposures that raise the risk of a multiple sclerosis diagnosis. Importantly, this increased risk cannot be entirely explained by infectious mononucleosis, pneumonia, or CNS infections.
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http://dx.doi.org/10.1093/brain/awab100DOI Listing
March 2021

Reduction of the risk of PML in natalizumab treated MS patients in Sweden: An effect of improved PML risk surveillance.

Mult Scler Relat Disord 2021 May 11;50:102842. Epub 2021 Feb 11.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Natalizumab (NTZ) treatment of multiple sclerosis (MS) has been associated with increased risk of progressive multifocal leukoencephalopathy (PML). The aim of the present study was to evaluate the impact of PML risk assessment on PML incidence in NTZ treated MS patients.

Methods: By using information from the population-based Swedish MS registry a retrospective cohort was established of patients treated with NTZ between 2006-2018. The effect on PML incidence before and after utilizing a risk management plan, including JC virus (JCV) serology, was analyzed.

Results: In December 2018, 804 PML cases associated with NTZ therapy of MS had been reported globally, including 9 cases from Sweden. The estimated PML incidence 2018 in Sweden and globally was 0.7 (0.3-1.4) and 4.15 (3.9-4.4) per 1,000 person years, respectively. In Sweden, JCV serology was introduced 2012 for PML risk assessment and the cumulative risk of PML was significantly lower 2012-2018 compared to the period 2006-2011 (p=0.042). The mean NTZ exposure time was 60.1 months (SD 37.2) in the first period (2006-2011) and 32.6 months (SD 22.0) in the second period (2012-2018). The number of patients treated with NTZ decreased, and the number of patients at increased risk of PML was 1.9 % at the end of the study period.

Conclusion: Since 2006 the incidence of PML associated with NTZ treatment of MS has decreased in Sweden. Our findings suggest that this reduction is due to an effective adoptation and adherence to the established risk management plan that implies switching patients at increased PML risk from NTZ to other highly efficacious therapies. A less pronounced decline in PML incidence has recently been observed in France, but not globally.
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http://dx.doi.org/10.1016/j.msard.2021.102842DOI Listing
May 2021

Deep Learning Corpus Callosum Segmentation as a Neurodegenerative Marker in Multiple Sclerosis.

J Neuroimaging 2021 05 15;31(3):493-500. Epub 2021 Feb 15.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background And Purpose: Corpus callosum atrophy is a sensitive biomarker of multiple sclerosis (MS) neurodegeneration but typically requires manual 2D or volumetric 3D-based segmentations. We developed a supervised machine learning algorithm, DeepnCCA, for corpus callosum segmentation and relate callosal morphology to clinical disability using conventional MRI scans collected in clinical routine.

Methods: In a prospective study of 553 MS patients with 704 acquisitions, 200 unique 2D T -weighted MRI scans were delineated to develop, train, and validate DeepnCCA. Comparative FreeSurfer segmentations were obtained in 504 3D T -weighted scans. Both FreeSurfer and DeepnCCA outputs were correlated with clinical disability. Using principal component analysis of the DeepnCCA output, the morphological changes were explored in relation to clinical disease burden.

Results: DeepnCCA and manual segmentations had high similarity (Dice coefficients 98.1 .11%, 89.3 .76%, for intracranial and corpus callosum area, respectively through 10-fold cross-validation). DeepnCCA had numerically stronger correlations with cognitive and physical disability as compared to FreeSurfer: Expanded disability status scale (EDSS) ±6 months (r = -.22 P = .002; r = -.17, P = .013), future EDSS (r = -.26, P<.001; r = -.17, P = .012), and future symbol digit modalities test (r = .26, P = .001; r = .24, P = .003). The corpus callosum became thinner with increasing cognitive and physical disability. Increasing physical disability, additionally, significantly correlated with a more angled corpus callosum.

Conclusions: DeepnCCA (https://github.com/plattenmichael/DeepnCCA/) is an openly available tool that can provide fast and accurate corpus callosum measurements applicable to large MS cohorts, potentially suitable for monitoring disease progression and therapy response.
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http://dx.doi.org/10.1111/jon.12838DOI Listing
May 2021

Creatinine and C-reactive protein in amyotrophic lateral sclerosis, multiple sclerosis and Parkinson's disease.

Brain Commun 2020 18;2(2):fcaa152. Epub 2020 Sep 18.

Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Serum creatinine and C-reactive protein have been proposed as potential biomarkers for neurodegenerative diseases, including amyotrophic lateral sclerosis, multiple sclerosis and Parkinson's disease. However, longitudinal studies investigating temporal patterns of these biomarkers, including the phase before diagnosis, are rare. We performed a case-control study including all newly diagnosed patients with amyotrophic lateral sclerosis ( = 525), multiple sclerosis ( = 1815) or Parkinson's disease ( = 3797) during 2006-2013 in Stockholm, Sweden, who participated in the Stockholm CREAtinine Measurements (SCREAM) project. For each case, we randomly selected up to five controls from SCREAM that were individually matched to the case by age, sex and county of residence ( = 2625 for amyotrophic lateral sclerosis,  = 9063 for multiple sclerosis and 18 960 for Parkinson's disease). We collected for both the cases and the controls testing results of serum creatinine and C-reactive protein performed by healthcare providers in Stockholm during the study period. Median levels of creatinine and C-reactive protein were visualized using locally weighted smoothing curves among cases and controls. A linear mixed model was also applied to explore temporal changes within an individual. Compared to controls, patients with amyotrophic lateral sclerosis had lower levels of creatinine from 2 years before diagnosis onwards. In contrast, patients with amyotrophic lateral sclerosis had lower levels of C-reactive protein before diagnosis but higher levels after diagnosis, compared to controls. Focusing the 2 years before to 2 years after diagnosis, patients with amyotrophic lateral sclerosis displayed statistically significantly decreasing level of creatinine from 1 year before diagnosis until 2 years after diagnosis, whereas increasing level of C-reactive protein from diagnosis until 2 years after diagnosis. There were no similar patterns noted among patients with multiple sclerosis or Parkinson's disease, or the controls of the three patient groups. Patients with amyotrophic lateral sclerosis display distinct temporal patterns of creatinine and C-reactive protein before and after diagnosis, compared to amyotrophic lateral sclerosis-free controls or patients with multiple sclerosis and Parkinson's disease.
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http://dx.doi.org/10.1093/braincomms/fcaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850290PMC
September 2020

Safety of Alemtuzumab and Autologous Hematopoietic Stem Cell Transplantation Compared to Noninduction Therapies for Multiple Sclerosis.

Neurology 2021 03 29;96(11):e1574-e1584. Epub 2021 Jan 29.

From the Department of Clinical Neuroscience (P.A., F.P.) and Clinical Epidemiology Division (P.A., T.F.), Department of Medicine Solna, Karolinska Institutet, Stockholm; Department of Neuroscience (J.B.), Uppsala University; Department of Clinical Neuroscience (J.L.), Institute of Neuroscience and Physiology, University of Gothenburg; and Academic Specialist Centre (F.P.), Stockholm Health Services, Sweden.

Objective: To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies.

Methods: We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection.

Results: We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclophosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed ≥6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference.

Conclusion: We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies.

Classification Of Evidence: This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
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http://dx.doi.org/10.1212/WNL.0000000000011545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032381PMC
March 2021

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects.

Sci Rep 2021 Jan 18;11(1):1669. Epub 2021 Jan 18.

Division of Physiotherapy, Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, and Academic Specialist Center, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.
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http://dx.doi.org/10.1038/s41598-021-81306-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814004PMC
January 2021

Quantification of Plasma Kynurenine Metabolites Following One Bout of Sprint Interval Exercise.

Int J Tryptophan Res 2020 10;13:1178646920978241. Epub 2020 Dec 10.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites suggested to be involved in a wide variety of diseases and disorders, however, technical challenges in reliably detecting these metabolites hampers cross-comparisons. The main objective of this study was to develop an accurate, robust and precise bioanalytical method for simultaneous quantification of ten plasma kynurenine metabolites. As a secondary aim, we applied this method on blood samples taken from healthy subjects conducting 1 session of sprint interval exercise (SIE). It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease, but also influences the peripheral and central concentrations of kynurenines. In line with this, we found that in healthy old adults ( = 10; mean age 64 years), levels of kynurenine increased 1 hour ( = .03) after SIE, while kynurenic acid (KYNA) concentrations were elevated after 24 hours ( = .02). In contrast, no significant changes after exercise were seen in young adults ( = 10; mean age 24 years). In conclusion, the described method performs well in reliably detecting all the analyzed metabolites in plasma samples. Furthermore, we also detected an age-dependent effect on the degree by which a single intense training session affects kynurenine metabolite levels.
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http://dx.doi.org/10.1177/1178646920978241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734489PMC
December 2020

Associations between autoimmune diseases and amyotrophic lateral sclerosis: a register-based study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 17;22(3-4):211-219. Epub 2020 Dec 17.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

To assess the associations of 43 autoimmune diseases with the subsequent risk of ALS and further evaluate the contribution of familial confounding to these associations. We conducted a nationwide register-based nested case-control study including 3561 ALS patients diagnosed during 1990-2013 in Sweden and 35,610 controls that were randomly selected from the general population and individually matched to the cases on age, sex, and county of birth. To evaluate the contribution of familial factors on the studied association, we additionally studied the first-degree relatives (siblings and children) of ALS patients and their controls. Patients with ALS had a 47% higher risk of being previously diagnosed with autoimmune disease (OR 1.47, 95% confidence interval [CI] 1.31-1.64), compared with controls. A positive association was noted for several autoimmune diseases, including myasthenia gravis, polymyositis or dermatomyositis, Guillain-Barre syndrome, type 1 diabetes diagnosed younger than 30 years, multiple sclerosis, and hypothyreosis. The increased risk of any autoimmune disease was greatest during the year before ALS diagnosis, likely due to misdiagnosis. A statistically significantly increased risk was also noted during 2-5 years, but not earlier, before ALS diagnosis. First-degree relatives of ALS patients had however no increased risk of autoimmune diseases compared with first-degree relatives of controls. Although it is difficult to completely remove the potential effects of misdiagnosis, there is likely a positive association between autoimmune disease (such as type 1 diabetes and multiple sclerosis) and ALS, which is not fully explained by shared familial confounding factors.
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http://dx.doi.org/10.1080/21678421.2020.1861022DOI Listing
May 2021

Effect of Vitamin D on Experimental Autoimmune Neuroinflammation Is Dependent on Haplotypes Comprising Naturally Occurring Allelic Variants of CIITA ().

Front Neurol 2020 13;11:600401. Epub 2020 Nov 13.

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

An increasing body of evidence associates low vitamin D levels with increased risk of multiple sclerosis (MS), suggesting the possibility of a gene-environment interaction for this environmental factor in MS pathogenesis. Moreover, it has been shown that vitamin D downregulates major histocompatibility complex (MHC) class II expression in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We here report about the impact of a dietary vitamin D supplementation on EAE in the rat strains having functionally relevant allelic variations in the () gene, a master regulator of MHC class II expression. Full length myelin oligodendrocyte glycoprotein (MOG)-EAE was induced in DA.PVG- congenic rats harboring the locus from PVG strain in the EAE- susceptible DA background, and compared to the parental strains. The congenic rats fed with either vitamin D supplemented, deprived or regular diet developed an intermediate clinical EAE phenotype, in contrast to DA and PVG strains. Immunopathological studies revealed vitamin D dose-dependent effect on demyelination and inflammatory infiltration of the central nervous system (CNS), expression of MHC class II and CIITA, as well as downregulation of a range of pro-inflammatory genes. Taken together, our findings demonstrate an impact of vitamin D on the target tissue pathology and peripheral immune response during EAE in DA.PVG- congenic strain. Thereby, our data provide evidence of a modulatory effect of vitamin D in context of genetic variances in the locus/ gene in MS-like neuroinflammation, with potential relevance for the human demyelinating disease.
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http://dx.doi.org/10.3389/fneur.2020.600401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693436PMC
November 2020

Cerebrospinal fluid brevican and neurocan fragment patterns in human traumatic brain injury.

Clin Chim Acta 2021 Jan 2;512:74-83. Epub 2020 Dec 2.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

Background: Altered levels of two extracellular matrix (ECM) proteoglycans, brevican and neurocan, have been found in brain injury models; however, their proteolytic processing in traumatic brain injury (TBI) remains unexplored. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a possible contributor to ECM remodelling following TBI. The aims of this study were to evaluate proteolytic brevican/neurocan patterns and ADAMTS-like activity in cerebrospinal fluid (CSF) in the context of TBI.

Materials And Methods: Forty-two acute TBI patients and 37 idiopathic normal pressure hydrocephalus (iNPH) patients were included in the analysis of tryptic brevican and neurocan peptides in CSF using parallel reaction monitoring mass spectrometry. Twenty-nine TBI and 36 iNPH patients were analysed for ADAMTS-like activity in CSF using a quenched fluorescent substrate.

Results: The majority of CSF concentrations of brevican peptides significantly decreased in TBI patients compared with the iNPH group (p ≤ 0.002), while ADAMTS-like activity increased (p < 0.0001). Two C-terminal brevican peptides strongly correlated with unfavourable outcome of TBI patients (rho = 0.85-0.93, p ≤ 0.001).

Conclusions: The decreased CSF concentrations of brevican peptides in TBI are associated with their increased degradation by ADAMTS enzymes. Furthermore, the N- and C-terminal parts of brevican are differentially regulated following TBI and may serve as outcome markers.
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http://dx.doi.org/10.1016/j.cca.2020.11.017DOI Listing
January 2021

A comparative study of tolerability and effects on immunoglobulin levels and CD19 cell counts with ocrelizumab vs low dose of rituximab in multiple sclerosis.

Mult Scler J Exp Transl Clin 2020 Oct-Dec;6(4):2055217320964505. Epub 2020 Oct 12.

Neuroimmunology Unit, Karolinska Institutet, Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden.

Background: Rituximab (RTX) and ocrelizumab (OCR) are two anti-CD20 biologics used in MS; however, comparisons on safety and efficacy are rare.

Objective: To compare treatment outcomes over the first year with RTX and OCR.

Methods: Retrospective cohort study comprising MS patients initiating RTX at the Karolinska University Hospital (Sweden; n = 311) and OCR at Rocky Mountain MS Clinic (Utah, USA; n = 161), respectively.

Results: Levels of immunoglobulin G measured in blood dropped 0.16 g/L (95% confidence interval 0.01 to 0.31) with each OCR infusion, but remained stable with RTX. In contrast, levels of immunoglobulin M decreased to a similar extent with both drugs. Ten and 15% of patients discontinued treatment with RTX and OCR, respectively (n.s), however, adverse events leading to treatment discontinuation were more common with OCR (6.8% vs 2.6%; p = 0.026). Only 3.1 and 1.6% discontinued OCR and RTX, respectively, due to lack of effect (n.s). The degree of B cell depletion was superior with OCR.

Conclusion: Overall, differences between the two treatments were small. Although the study design precludes robust conclusions regarding the risk-benefit with the studied therapies, our findings indicate that the tolerability and safety with RTX is not inferior to OCR.
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http://dx.doi.org/10.1177/2055217320964505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556182PMC
October 2020

Dynamics of cerebrospinal fluid levels of matrix metalloproteinases in human traumatic brain injury.

Sci Rep 2020 10 22;10(1):18075. Epub 2020 Oct 22.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Matrix metalloproteinases (MMPs) are extracellular enzymes involved in the degradation of extracellular matrix (ECM) proteins. Increased expression of MMPs have been described in traumatic brain injury (TBI) and may contribute to additional tissue injury and blood-brain barrier damage. The objectives of this study were to determine longitudinal changes in cerebrospinal fluid (CSF) concentrations of MMPs after acute TBI and in relation to clinical outcomes, with patients with idiopathic normal pressure hydrocephalus (iNPH) serving as a contrast group. The study included 33 TBI patients with ventricular CSF serially sampled, and 38 iNPH patients in the contrast group. Magnetic bead-based immunoassays were utilized to measure the concentrations of eight MMPs in ventricular human CSF. CSF concentrations of MMP-1, MMP-3 and MMP-10 were increased in TBI patients (at baseline) compared with the iNPH group (p < 0.001), while MMP-2, MMP-9 and MMP-12 did not differ between the groups. MMP-1, MMP-3 and MMP-10 concentrations decreased with time after trauma (p = 0.001-0.04). Increased concentrations of MMP-2 and MMP-10 in CSF at baseline were associated with an unfavourable TBI outcome (p = 0.002-0.02). Observed variable pattern of changes in MMP concentrations indicates that specific MMPs serve different roles in the pathophysiology following TBI, and are in turn associated with clinical outcomes.
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http://dx.doi.org/10.1038/s41598-020-75233-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582923PMC
October 2020

Disease activity in pregnancy and postpartum in women with MS who suspended rituximab and natalizumab.

Neurol Neuroimmunol Neuroinflamm 2020 11 21;7(6). Epub 2020 Oct 21.

From the Department of Medicine (N.R., T.F.), Solna, Clinical Epidemiology Division, Karolinska Institutet; Department of Clinical Neuroscience (F.P., K.A.M., K.F.), Karolinska Institutet; Centrum for Neurology (F.P., K.F.), Academical Specialist Center, Stockholm, Sweden; Southern California Permanente Medical Group/Kaiser Permanente (A.M.L.-G.), Pasadena, CA; and Centre for Molecular Medicine (K.A.M.), Karolinska University Hospital, Stockholm, Sweden.

Objective: To evaluate risks of disease reactivity during pregnancy and postpartum following rituximab (RTX) and natalizumab (NTZ) suspension in women with MS.

Methods: An observational cohort study of all women with MS disease onset before childbirth between 2006 and 2017. Women were identified through the Swedish MS Registry, a nationwide clinical register, with substratification into 3 groups: women who suspended RTX and NTZ within 6 months before conception and women who were not treated with any disease-modifying treatment (DMT) within 1 year of conception. The primary outcome was the annualized relapse rate (ARR) during pregnancy and 1 year postpartum.

Results: We identified 2,386 women with MS onset before a live birth; of these, 76 women suspended RTX and 53 suspended NTZ, and 457 were untreated within 1 year before conception. In all women, regardless of the treatment type, the ARR declined from 0.05-0.04 prepregnancy to 0.03-0.02 during pregnancy, returning to prepregnancy rates at 3-6 months (0.05) postpartum. In the suspended cohort, 76% (98/129) of women resumed a DMT after delivery. The relapse rate 1 year postpartum was significantly higher in the suspended NTZ women compared with the suspended RTX women (adjusted rate ratio [aRR] 7.65, 95% CI 2.47-23.6) and was lower in the suspended RTX women compared with the untreated women (aRR 0.21, 95% CI 0.08-0.61).

Conclusion: Disease reactivity during the postpartum period was lower among women with MS who suspended RTX before pregnancy, relative to those who suspended NTZ and untreated women. These findings suggest that RTX may exert long-acting effects on MS disease activity that encompass pregnancy and postpartum periods.

Classification Of Evidence: This study provides Class IV evidence that in patients with MS who were on treatment before pregnancy, RTX reduces clinical disease activity compared with NTZ in the postpartum period.
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http://dx.doi.org/10.1212/NXI.0000000000000903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641107PMC
November 2020

The DQB103:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis.

Front Neurol 2020 4;11:993. Epub 2020 Sep 4.

Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, Sweden.

Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB103:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB103:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB103:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB103:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB103:02 allele effect is modified by the presence of MS.
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http://dx.doi.org/10.3389/fneur.2020.00993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500133PMC
September 2020

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus.

Ann Neurol 2020 12 6;88(6):1244-1250. Epub 2020 Oct 6.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244-1250.
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http://dx.doi.org/10.1002/ana.25908DOI Listing
December 2020

Non-infectious comorbidity in patients with multiple sclerosis: A national cohort study in Sweden.

Mult Scler J Exp Transl Clin 2020 Jul-Sep;6(3):2055217320947761. Epub 2020 Aug 14.

Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University Hospital and Örebro University, Örebro, Sweden.

Background: Comorbidity is of significant concern in multiple sclerosis (MS). Few population-based studies have reported conditions occurring in MS after diagnosis, especially in contemporary cohorts.

Objective: To explore incident comorbidity, mortality and hospitalizations in MS, stratified by age and sex.

Methods: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years) and 61,828 matched MS-free individuals were identified between 1 January 2008 and 31 December 2016, using national registers. Incidence rates (IRs) and incidence rate ratios (IRRs) with 95% CI were calculated for each outcome.

Results: IRs of cardiovascular disease (CVD) were higher among MS patients than MS-free individuals, (major adverse CVD: IRR 1.42; 95% CI 1.12-1.82; hemorrhagic/ischemic stroke: 1.46; 1.05-2.02; transient ischemic attack: 1.65; 1.09-2.50; heart failure: 1.55; 1.15-2.10); venous thromboembolism: 1.42; 1.14-1.77). MS patients also had higher risks of several non-CVDs such as autoimmune conditions (IRR 3.83; 3.01-4.87), bowel dysfunction (2.16; 1.86-2.50), depression (2.38; 2.11-2.68), and fractures (1.32; 1.19-1.47), as well as being hospitalized and to suffer from CVD-related deaths ((1.91; 1.00-3.65), particularly in females (3.57; 1.58-8.06)).

Conclusion: MS-patients experience a notable comorbidity burden which emphasizes the need for integrated disease management in order to improve patient care and long-term outcomes of MS.
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http://dx.doi.org/10.1177/2055217320947761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430080PMC
August 2020

Neurological manifestations of coronavirus infections - a systematic review.

Ann Clin Transl Neurol 2020 10 27;7(10):2057-2071. Epub 2020 Aug 27.

Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.

To optimize diagnostic workup of the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, we systematically reviewed neurological and neuroradiological manifestations of SARS-CoV-2 and all other known human coronavirus species (HCoV). Which lessons can we learn? We identified relevant publications (until 26 July 2020) using systematic searches in PubMed, Web of Science, and Ovid EMBASE with predefined search strings. A total of 4571 unique publications were retrieved, out of which 378 publications were selected for in-depth analysis by two raters, including a total of 17549 (out of which were 14418 SARS-CoV-2) patients. Neurological complications and associated neuroradiological manifestations are prevalent for all HCoVs (HCoV-229E, HKU1, NL63, OC43, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-1, and SARS-CoV-2). Moreover there are similarities in symptomatology across different HCoVs, particularly between SARS-CoV-1 and SARS-CoV-2. Common neurological manifestations include fatigue, headache, and smell/taste disorders. Additionally, clinicians need to be attentive for at least five classes of neurological complications: (1) Cerebrovascular disorders including ischemic stroke and macro/micro-hemorrhages, (2) encephalopathies, (3) para-/postinfectious immune-mediated complications such as Guillain-Barré syndrome and acute disseminated encephalomyelitis, (4) (meningo-)encephalitis, potentially with concomitant seizures, and (5) neuropsychiatric complications such as psychosis and mood disorders. Our systematic review highlights the need for vigilance regarding neurological complications in patients infected by SARS-CoV-2 and other HCoVs, especially since some complications may result in chronic disability. Neuroimaging protocols should be designed to specifically screen for these complications. Therefore, we propose practical imaging guidelines to facilitate the diagnostic workup and monitoring of patients infected with HCoVs.
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http://dx.doi.org/10.1002/acn3.51166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461163PMC
October 2020

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis.

Nat Commun 2020 08 13;11(1):4071. Epub 2020 Aug 13.

Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, 17177, Stockholm, Sweden.

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.
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http://dx.doi.org/10.1038/s41467-020-17871-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426940PMC
August 2020

Is the treatment of myasthenia gravis improving? Why not ask our patients?

Neurology 2020 09 5;95(12):509-510. Epub 2020 Aug 5.

From the Karolinska University Hospital (F.P.), Stockholm, Sweden; and University at Buffalo (G.I.W.), NY.

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http://dx.doi.org/10.1212/WNL.0000000000010578DOI Listing
September 2020

Infections in patients with multiple sclerosis: A national cohort study in Sweden.

Mult Scler Relat Disord 2020 Oct 23;45:102420. Epub 2020 Jul 23.

Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University Hospital and Örebro University, Fakultetsgatan 1, 701 82 Örebro, Sweden; Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.

Background: Multiple sclerosis (MS) patients have an increased risk of infections, but few population-based studies have reported infections occurring in MS in the years immediately after diagnosis.

Objective: To explore incident infections in MS, stratified by age and sex.

Methods: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years), matched at diagnosis with 61,828 matched MS-free individuals were identified between 1st January 2008 and 31st December 2016, using national registers. Incidence rates (IR) and incidence rate ratios (IRR) with 95% CI were calculated for each outcome.

Results: The IRRs were 2.54 (95% CI 2.28-2.83) for first serious infection and 1.61 (1.52-1.71) for first non-serious infection. Compared with MS-free individuals, MS patients had higher IRs for skin, respiratory/throat infections, pneumonia/influenza, bacterial, viral, and fungal infections, with the highest IRR observed for urinary tract/kidney infections (2.44; 2.24-2.66). The cumulative incidence for most of these infections was higher among MS patients than MS-free individuals, both 0 to <5 and 5 to <9 years after index date.

Conclusion: The burden of infections around the time of MS diagnosis and subsequent infection risk, underscore the need for careful considerations regarding the risk-benefit across different disease-modifying therapies.
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http://dx.doi.org/10.1016/j.msard.2020.102420DOI Listing
October 2020

Enlarged perivascular spaces in multiple sclerosis on magnetic resonance imaging: a systematic review and meta-analysis.

J Neurol 2020 Nov 13;267(11):3199-3212. Epub 2020 Jun 13.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Perivascular spaces can become detectable on magnetic resonance imaging (MRI) upon enlargement, referred to as enlarged perivascular spaces (EPVS) or Virchow-Robin spaces. EPVS have been linked to small vessel disease. Some studies have also indicated an association of EPVS to neuroinflammation and/or neurodegeneration. However, there is conflicting evidence with regards to their potential as a clinically relevant imaging biomarker in multiple sclerosis (MS).

Methods: To perform a systematic review and meta-analysis of EPVS as visualized by MRI in MS. Nine out of 299 original studies addressing EPVS in humans using MRI were eligible for the systematic review and meta-analysis including a total of 457 MS patients and 352 control subjects.

Results: In MS, EPVS have been associated with cognitive decline, contrast-enhancing MRI lesions, and brain atrophy. Yet, these associations were not consistent between studies. The meta-analysis revealed that MS patients have greater EPVS prevalence (odds ratio = 4.61, 95% CI = [1.84; 11.60], p = 0.001) as well as higher EPVS counts (standardized mean difference [SMD] = 0.46, 95% CI = [0.26; 0.67], p < 0.001) and larger volumes (SMD = 0.88, 95% CI = [0.19; 1.56], p = 0.01) compared to controls.

Conclusions: Available literature suggests a higher EPVS burden in MS patients compared to controls. The association of EPVS to neuroinflammatory or -degenerative pathology in MS remains inconsistent. Thus, there is currently insufficient evidence supporting EPVS as diagnostic and/or prognostic marker in MS. In order to benefit future comparisons of studies, we propose recommendations on EPVS assessment standardization in MS. PROSPERO No: CRD42019133946.
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http://dx.doi.org/10.1007/s00415-020-09971-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577911PMC
November 2020

Diagnostic accuracy of intrathecal kappa free light chains compared with OCBs in MS.

Neurol Neuroimmunol Neuroinflamm 2020 07 11;7(4). Epub 2020 Jun 11.

From the Department of Neurobiology, Care Sciences and Society (F.D.), Department of Clinical Neuroscience (B.E., F.A.N., T.O., M.K., M.A.H., F.P.), and Department of Laboratory Medicine (M.H.), Karolinska Institutet; Department of Clinical Chemistry (F.D., A.S., M.H.) and Department of Neurology (B.E., T.O., M.K., M.A.H., F.P.), Karolinska University Hospital; and Unit of Medical Statistics (D.O.), Department of Learning, Informatics, Management and Ethics (LIME), Karolinska Institutet, Stockholm, Sweden.

Objective: To determine what kappa free light chain (KFLC) metric has the highest capacity to separate healthy patients from patients with MS, we evaluated the sensitivity, specificity, and the overall diagnostic accuracy of 4 different KFLC metrics. To assess the usefulness of KFLC in the diagnostics of MS, we compared the different KFLC metrics with oligoclonal bands (OCBs), the current gold standard biochemical method to demonstrate intrathecal antibody production.

Methods: CSF and plasma were collected from patients with confirmed or suspected MS, other neurological diseases, as well as symptomatic and healthy controls between May 2017 and May 2018 (n = 335) at the Department of Neurology, Karolinska University Hospital, as part of routine diagnostic workup. KFLC analysis and isoelectric focusing for the detection of oligoclonal bands (OCB) were determined and correlated with diagnosis. Receiver operating characteristic (ROC) curve analysis was used to determine accuracy.

Results: OCBs yielded a sensitivity of 87% and a specificity of 100%. All KFLC metrics showed a high sensitivity (89%-95%) and specificity (95%-100%). Using the optimal cutoff according to the Youden Index resulted for the KFLC intrathecal fraction in a cutoff of -0.41 with a sensitivity of 95% and a specificity of 97% and for CSF KFLC/CSF albumin with a cutoff of 1.93 × 10 with a sensitivity of 94% and specificity of 100%.

Conclusion: All evaluated KFLC metrics have excellent accuracy, and both KFLC intrathecal fraction and CSF KFLC/CSF albumin are at least as good as OCB in separating patients with MS from a control group.

Classification Of Evidence: This study provides Class III evidence that CSF KFLC accurately distinguishes patients with MS from healthy controls.
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http://dx.doi.org/10.1212/NXI.0000000000000775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309528PMC
July 2020

CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects.

IBRO Rep 2020 Jun 13;8:136-142. Epub 2020 Apr 13.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms.
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http://dx.doi.org/10.1016/j.ibror.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262376PMC
June 2020

Inflammation-related plasma and CSF biomarkers for multiple sclerosis.

Proc Natl Acad Sci U S A 2020 06 26;117(23):12952-12960. Epub 2020 May 26.

Neuroimmunology Unit, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska University Hospital, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable 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 similar 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 comparison 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 associated with disease duration particularly in patients who had secondary progressive disease ( < 4 × 10, < 4 × 10), and plasma CCL20 was associated with disease severity ( = 4 × 10), 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 importance is the set of markers discovered in blood, where validated biomarkers are lacking.
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http://dx.doi.org/10.1073/pnas.1912839117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293699PMC
June 2020

Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis.

Neurology 2020 06 20;94(23):e2457-e2467. Epub 2020 May 20.

From the Department of Clinical Neuroscience (A.M., P.S., M.K., F.P., T.O., I.K.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Karolinska Institutet; Centre for Molecular Medicine (A.M., P.S., M.K., F.P., T.O., I.K.), Karolinska University Hospital, Stockholm, Sweden; Departments of Medicine, Biomedicine, and Clinical Research (D.L., C.B., Z.M., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel; Clinical Trial Unit (P.B.), Department of Clinical Research, University Hospital Basel, University of Switzerland; Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Gothenburg; Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.

Objective: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.

Methods: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).

Results: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS ( < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.

Conclusions: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.
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http://dx.doi.org/10.1212/WNL.0000000000009571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455371PMC
June 2020