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Sökning: WFRF:(Otto Markus) > Medicin och hälsovetenskap

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1.
  • Lill, Christina M., et al. (författare)
  • The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
  • 2015
  • Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:12, s. 1407-1416
  • Tidskriftsartikel (refereegranskat)abstract
    • A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Ab42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 x 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Ab42 suggesting that TREM2's role in AD may involve tau dysfunction. (C) 2015 The Alzheimer's Association.
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  • Brenner, David, et al. (författare)
  • Hot-spot KIF5A mutations cause familial ALS
  • 2018
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
  • Tidskriftsartikel (refereegranskat)abstract
    • Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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  • Mattsson, Niklas, 1979, et al. (författare)
  • The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
  • 2011
  • Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4, s. 386-395.e6
  • Tidskriftsartikel (refereegranskat)abstract
    • The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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6.
  • Spitzer, Philipp, et al. (författare)
  • cNEUPRO: Novel Biomarkers for Neurodegenerative Diseases.
  • 2010
  • Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2010
  • Forskningsöversikt (refereegranskat)abstract
    • "clinical NEUroPROteomics of neurodegenerative diseases" (cNEUPRO) is a Specific Targeted Research Project (STREP) within the sixth framework program of the European Commission dedicated to the search for novel biomarker candidates for Alzheimer's disease and other neurodegenerative diseases. The ultimate goal of cNEUPRO is to identify one or more valid biomarker(s) in blood and CSF applicable to support the early and differential diagnosis of dementia disorders. The consortium covers all steps required for the discovery of novel biomarker candidates such as acquisition of high quality CSF and blood samples from relevant patient groups and controls, analysis of body fluids by various methods, and finally assay development and assay validation. Here we report the standardized procedures for diagnosis and preanalytical sample-handling within the project, as well as the status of the ongoing research activities and some first results.
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7.
  • van Rheenen, Wouter, et al. (författare)
  • Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
  • 2016
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
  • Tidskriftsartikel (refereegranskat)abstract
    • To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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8.
  • Wibring, Kristoffer, et al. (författare)
  • Guideline adherence among prehospital emergency nurses when caring for patients with chest pain : a prospective cohort study
  • 2021
  • Ingår i: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. - : BioMed Central Ltd. - 1757-7241. ; 29:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The emergency medical services (EMS) use guidelines to describe optimal patient care for a wide range of clinical conditions and symptoms. The intent is to guide personnel to provide patient care in line with best practice. The aim of this study is to describe adherence to such guidelines among prehospital emergency nurses (PENs) when caring for patients with chest pain. Objective: To describe guideline adherence among PENs when caring for patients with chest pain. To investigate whether guideline adherence is associated with patient age, sex or final diagnosis of acute myocardial infarction on hospital discharge. Methods: Guideline adherence in terms of patient examination and pharmaceutical treatment was analysed in a cohort of 2092 EMS missions carried out in 2018 in Region Halland, Sweden. Multivariate regression was used to describe how guideline adherence is associated with patient age, sex and diagnosis on hospital discharge. Results: Guideline adherence was high regarding examination of vital signs (93%) and electrocardiogram (ECG) registration (96%) but lower in terms of pharmaceutical treatment (ranging from 28 to 90%). Adherence was increased in cases in which the patient ended up with acute myocardial infarction (AMI) as diagnosis on discharge. Patients with AMI were given acetylsalicylic acid by PENs in 50% of cases. Women were less likely than men to receive treatment with acetylsalicylic acid and oxycodone. Conclusions: Guideline adherence among PENs when caring for patients with chest pain is satisfactory in terms vital signs and ECG registration. Regarding pharmaceutical treatment guideline adherence is defective. Improved adherence is mainly associated with male sex in patients and a diagnosis of AMI on hospital discharge. Defective adherence excludes measures known to improve patients’ prognoses such as treatment with acetylsalicylic acid. © 2021, The Author(s).
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9.
  • Ezer, Shlomit, et al. (författare)
  • Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity
  • 2022
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:3, s. 872-878
  • Tidskriftsartikel (refereegranskat)abstract
    • Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.
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10.
  • Brockmann, Sarah J., et al. (författare)
  • CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency
  • 2018
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 27:4, s. 706-715
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
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