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  • Warnke, C., et al. (författare)
  • Changes to anti-JCV antibody levels in a Swedish national MS cohort
  • 2013
  • Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 84:11, s. 1199-1205
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). Objective To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. Methods An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. Results Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. Conclusions Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted.
  • Weller, B, et al. (författare)
  • 2015
  • Ingår i: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY. - : BMJ. - 0022-3050 .- 1468-330X. ; 86:11
  • Konferensbidrag (övrigt vetenskapligt)abstract
    • Teriflunomide is an immunomodulator known to decrease the proliferation of stimulated lymphocytes via inhibition of dihydro-orotate dehydrogenase. Lymphocyte/neutrophil counts were assessed in pooled data from one phase 2 and three phase 3 (TEMSO, TOWER, and TOPIC) placebo-controlled studies.MethodsPatients were randomized to receive once-daily teriflunomide 14mg (n=1002), 7mg (n=1045), or placebo (n=997). Blood samples were collected throughout the studies.ResultsMean baseline lymphocyte and neutrophil counts were similar across groups. Small decreases in mean lymphocyte and neutrophil counts occurred within the first 12 weeks (lymphocytes) or 6 weeks (neutrophils) of treatment, and stabilized within the normal range for most patients thereafter. Patients with neutrophil counts <1×10^9^/L were to discontinue treatment; 11 (1.1%; 14 mg), 8 (0.8%; 7 mg), and 1 (0.1%; placebo) patients discontinued due to neutropenia or neutrophil count decrease as per protocol requirements. Neutropenia was reported as a serious adverse event (SAE) in 7 (0.7%; 14 mg), 2 (0.2%; 7 mg), and 3 (0.3%; placebo) patients; there were no lymphopenia SAEs. No link between neutrophil or lymphocyte count decreases and infection was observed.ConclusionsThese data demonstrate that teriflunomide has small, reversible effects on lymphocyte/neutrophil counts, with no increase in infection risk observed. (Study supported by Genzyme, a Sanofi company).
  • Willemse, SW, et al. (författare)
  • UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target
  • 2023
  • Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050.
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in theUNC13Agene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants inUNC13Alead to the inclusion of a cryptic exon inUNC13Amessenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion ofUNC13Aleads to impaired neurotransmission. Recent discoveries have identifiedUNC13Aas a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate inUNC13Acases now underway and future approaches with antisense oligonucleotides currently under consideration. ConsideringUNC13Ais a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery ofUNC13Aas a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.
  • Wilson, Katherine M, et al. (författare)
  • Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.
  • 2022
  • Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 93:7, s. 761-771
  • Tidskriftsartikel (refereegranskat)abstract
    • A GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay.We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72-associated FTD/ALS.We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts.
  • Wilson, Lindsay, et al. (författare)
  • Understanding the relationship between cognitive performance and function in daily life after traumatic brain injury
  • 2020
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X.
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Cognitive impairment is a key cause of disability after traumatic brain injury (TBI) but relationships with overall functioning in daily life are often modest. The aim is to examine cognition at different levels of function and identify domains associated with disability.METHODS: 1554 patients with mild-to-severe TBI were assessed at 6 months post injury on the Glasgow Outcome Scale-Extended (GOSE), the Short Form-12v2 and a battery of cognitive tests. Outcomes across GOSE categories were compared using analysis of covariance adjusting for age, sex and education.RESULTS: Overall effect sizes were small to medium, and greatest for tests involving processing speed (ηp2 0.057-0.067) and learning and memory (ηp2 0.048-0.052). Deficits in cognitive performance were particularly evident in patients who were dependent (GOSE 3 or 4) or who were unable to participate in one or more major life activities (GOSE 5). At higher levels of function (GOSE 6-8), cognitive performance was surprisingly similar across categories. There were decreases in performance even in patients reporting complete recovery without significant symptoms. Medium to large effect sizes were present for summary measures of cognition (ηp2 0.111), mental health (ηp2 0.131) and physical health (ηp2 0.252).CONCLUSIONS: This large-scale study provides novel insights into cognitive performance at different levels of disability and highlights the importance of processing speed in function in daily life. At upper levels of outcome, any influence of cognition on overall function is markedly attenuated and differences in mental health are salient.
  • Wu, J, et al. (författare)
  • Influence of oral tobacco versus smoking on multiple sclerosis disease activity and progression
  • 2023
  • Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050.
  • Tidskriftsartikel (refereegranskat)abstract
    • We aimed to study the influence of smoking habits, exposure to passive smoking and snuff use on disease progression, cognitive performance and quality of life in patients with multiple sclerosis (MS).Patients from two population-based case–control studies were categorised based on tobacco exposure at diagnosis and were followed up to 15 years post diagnosis through the Swedish MS registry (n=9089) regarding changes in Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale 29 and Symbol Digit Modalities Test. We used linear mixed models to analyse long-term changes, and Cox regression models with 95% CI using 24-week confirmed disability worsening, reaching EDSS 3 and EDSS 4, respectively, physical and psychological worsening and cognitive disability worsening as end points. The influence of smoking cessation post diagnosis was also investigated.ResultsCompared with non-smokers, current smokers had a faster EDSS progression (βcurrent smoking×time=0.03, 95% CI 0.02 to 0.04). A faster EDSS progression was also associated with passive smoking (βcurrent passive smoking×time=0.04, 95% CI 0.03 to 0.06). Smoke exposure negatively impacted all secondary outcomes. Those who continued smoking had worse outcomes than those who stopped smoking post diagnosis. Snuff users had a more favourable EDSS progression, compared with never users.ConclusionsOur findings indicate that both smoking and passive smoking have a negative influence on MS and that smoking cessation post diagnosis may be an important secondary preventive measure. Snuff use was associated with slower disease progression, suggesting that nicotine replacement therapy could be an attractive way to increase the chance of quitting smoking among patients with MS.
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