| 91. |
- Lee, Teresa, et al.
(författare)
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Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:9, s. 1697-1700
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.
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| 92. |
- Lehmann, Patrick M, et al.
(författare)
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A numerical human brain phantom for dynamic glucose-enhanced (DGE) MRI : On the influence of head motion at 3T
- 2023
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Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 1522-2594 .- 0740-3194. ; 89:5, s. 1871-1887
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Dynamic glucose-enhanced (DGE) MRI relates to a group of exchange-based MRI techniques where the uptake of glucose analogues is studied dynamically. However, motion artifacts can be mistaken for true DGE effects, while motion correction may alter true signal effects. The aim was to design a numerical human brain phantom to simulate a realistic DGE MRI protocol at 3T that can be used to assess the influence of head movement on the signal before and after retrospective motion correction.METHODS: MPRAGE data from a tumor patient were used to simulate dynamic Z-spectra under the influence of motion. The DGE responses for different tissue types were simulated, creating a ground truth. Rigid head movement patterns were applied as well as physiological dilatation and pulsation of the lateral ventricles and head-motion-induced B 0 -changes in presence of first-order shimming. The effect of retrospective motion correction was evaluated. RESULTS: Motion artifacts similar to those previously reported for in vivo DGE data could be reproduced. Head movement of 1 mm translation and 1.5 degrees rotation led to a pseudo-DGE effect on the order of 1% signal change. B 0 effects due to head motion altered DGE changes due to a shift in the water saturation spectrum. Pseudo DGE effects were partly reduced or enhanced by rigid motion correction depending on tissue location. CONCLUSION: DGE MRI studies can be corrupted by motion artifacts. Designing post-processing methods using retrospective motion correction including B 0 correction will be crucial for clinical implementation. The proposed phantom should be useful for evaluation and optimization of such techniques.
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| 93. |
- Lulé, Dorothée E., et al.
(författare)
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Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder
- 2020
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 91:11, s. 1195-1200
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Tidskriftsartikel (refereegranskat)abstract
- Background: A mutation in C9orf72 constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).Methods: In total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72 and 15 with SOD1 mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.Results: C9orf72 expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1 mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.Discussion: Reduced verbal fluency performance seems to be a distinct clinical feature of C9orf72 carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72 carriers.
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| 94. |
- Malmborg, Jens, et al.
(författare)
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Prediction models of free-field vibrations from railway traffic
- 2017
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Ingår i: COMPDYN 2017 : 6 th ECCOMAS Thematic Conference on Computational Methods in Structural Dynamics and Earthquake Engineering - 6 th ECCOMAS Thematic Conference on Computational Methods in Structural Dynamics and Earthquake Engineering. - Athens : Institute of Structural Analysis and Antiseismic Research School of Civil Engineering National Technical University of Athens (NTUA) Greece. ; , s. 4810-4820
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Konferensbidrag (refereegranskat)abstract
- Many cities experience an increasing population leading to a need for urban densification. In these cities, unused land close to railways will have to be developed with new residential and office buildings. The infrastructural demand will also increase, resulting in heavily trafficked roads and railways close to w here people work and live. Annoyance from traffic-induced vibrations and noise is expected to be a growing issue. To predict the level of vibration and noise in buildings caused by railway and road traffic, calculation models are needed.In the present pa per, a simplified prediction model is briefly described. This prediction model is based on the assumption that the ground and railway embankment can be described in an axisymmetric model , to provide the transfer functions between the track and the free-field . In the paper, the error that arise by assuming axisymmetric response is studied by comparing the response in a three-dimensional finite-element model. Transfer functions at several positions in the free-field are compared
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| 95. |
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| 96. |
- McLoon, Linda K, et al.
(författare)
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Wnt and Extraocular Muscle Sparing in Amyotrophic Lateral Sclerosis
- 2014
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Ingår i: Investigative Ophthalmology and Visual Science. - : ARVO, The Association for Reserach in Vision and Ophthalmology. - 0146-0404 .- 1552-5783. ; 55:9, s. 5482-5496
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOMs in ALS.METHODS: EOM and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS patients and the SOD1G93A mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and beta-catenin.RESULTS: All four Wnt isoforms were expressed in most axon profiles in all human EOMs. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression was also seen, except for Wnt7a, where expression was elevated. In the SOD1G93A mouse, all 4 Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to age matched controls. Beta-catenin was activated in a subset of myofibers in EOM and limb muscle in all patients.CONCLUSIONS: The differences in Wnt expression in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for Wnt signaling in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.
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| 97. |
- Mueller, Kathrin, et al.
(författare)
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Comprehensive analysis of the mutation spectrum in 301 German ALS families
- 2018
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 89:8, s. 817-827
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
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| 98. |
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| 99. |
- Nordin, Angelica, et al.
(författare)
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Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation : a large multinational screening study
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa UK Limited. - 2167-8421 .- 2167-9223. ; 18:3-4, s. 256-264
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Tidskriftsartikel (refereegranskat)abstract
- A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele. In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.
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| 100. |
- Oliveros, Carl H., et al.
(författare)
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Earth history and the passerine superradiation
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:16, s. 7916-7925
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Tidskriftsartikel (refereegranskat)abstract
- Avian diversification has been influenced by global climate change, plate tectonic movements, and mass extinction events. However, the impact of these factors on the diversification of the hyper-diverse perching birds (passerines) is unclear because family level relationships are unresolved and the timing of splitting events among lineages is uncertain. We analyzed DNA data from 4,060 nuclear loci and 137 passerine families using concatenation and coalescent approaches to infer a comprehensive phylogenetic hypothesis that clarifies relationships among all passerine families. Then, we calibrated this phylogeny using 13 fossils to examine the effects of different events in Earth history on the timing and rate of passerine diversification. Our analyses reconcile passerine diversification with the fossil and geological records; suggest that passerines originated on the Australian landmass ∼47 Ma; and show that subsequent dispersal and diversification of passerines was affected by a number of climatological and geological events, such as Oligocene glaciation and inundation of the New Zealand landmass. Although passerine diversification rates fluctuated throughout the Cenozoic, we find no link between the rate of passerine diversification and Cenozoic global temperature, and our analyses show that the increases in passerine diversification rate we observe are disconnected from the colonization of new continents. Taken together, these results suggest more complex mechanisms than temperature change or ecological opportunity have controlled macroscale patterns of passerine speciation.
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