| 11. |
- 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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| 12. |
- Sinding, Mikkel-Holger S., et al.
(författare)
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Arctic-adapted dogs emerged at the Pleistocene-Holocene transition
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 368:6498
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Tidskriftsartikel (refereegranskat)abstract
- Although sled dogs are one of the most specialized groups of dogs, their origin and evolution has received much less attention than many other dog groups. We applied a genomic approach to investigate their spatiotemporal emergence by sequencing the genomes of 10 modern Greenland sled dogs, an similar to 9500-year-old Siberian dog associated with archaeological evidence for sled technology, and an similar to 33,000-year-old Siberian wolf. We found noteworthy genetic similarity between the ancient dog and modern sled dogs. We detected gene flow from Pleistocene Siberian wolves, but not modern American wolves, to present-day sled dogs. The results indicate that the major ancestry of modern sled dogs traces back to Siberia, where sled dog-specific haplotypes of genes that potentially relate to Arctic adaptation were established by 9500 years ago.
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| 13. |
- Behzadi, Arvin, et al.
(författare)
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Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics.
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.
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| 14. |
- Cudkowicz, Merit, et al.
(författare)
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Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study) : a randomised, double-blind, placebo-controlled phase 3 trial
- 2021
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 821-831
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function.METHODS: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately.FINDINGS: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis.INTERPRETATION: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.FUNDING: Orion Corporation.
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| 15. |
- Decarvalho, Mamede, et al.
(författare)
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Peripheral neuropathy in ALS : Phenotype association
- 2021
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 92:10, s. 1133-1134
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative disease mainly affecting upper and lower motor neurons but also causing multisystem involvement, in particular, associated with cognitive changes. Minor sensory fibre dysfunction has been described in the past1 and confirmed in recent studies.2 In a multicentre study investigating a population of 88 patients with ALS, the ESTEEM group (a European Telematic Project for quality assurance within Clinical Neurophysiology) reported sensory polyneuropathy (PNP) in 12.5% of the patients, not influenced by age, disease duration and onset region.In this study, we aimed to readdress prevalence of and risk factors for PNP in a larger population of patients with ALS. A large number of variables, including gene mutations, were assessed.
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| 16. |
- Diekmann, Kristin, et al.
(författare)
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Impact of comorbidities and co-medication on disease onset and progression in a large German ALS patient group
- 2020
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Ingår i: Journal of Neurology. - : Springer. - 0340-5354 .- 1432-1459. ; 267:7, s. 2130-2141
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with loss of muscle function. The pathogenesis is still unclear and the heterogeneity of ALS phenotypes is huge. We investigated a large population of ALS patients and controls concerning comorbidities and medications to detect specific risk or protective factors regarding onset and progression of ALS.Methods: We investigated a cohort of 200 ALS patients pro- and retrospectively compared to a control group. For comparison of frequencies of comorbidities and medication intake, uni- and multivariate binary logistic regressions were performed. To analyze the influence of comorbidities and medication on the progression of ALS, we used linear regression analysis.Results: ALS patients showed a relevantly higher prevalence of strokes and depression compared to controls. Moreover, ALS patients reported relevantly more often regular physical activity and their BMI was lower. The coexistence of coronary heart disease was associated with a relevantly faster disease progression. Intake of contraceptives was relevantly higher in controls compared with ALS patients.Conclusions: Our results suggest stroke, lower BMI, and regular physical activity as risk factors for ALS. Strokes could be a possible trigger of the pathogenetic pathway of ALS and the lower BMI with consecutively lower rate of hyperlipidemia supports the hypothesis of premorbid hypermetabolism in ALS patients. Coexistence of coronary heart disease possibly has a negative influence on respiratory involvement. Contraceptives could be beneficial due to a protective effect of estrogen. Information on influencing factors can help to elucidate the pathogenesis of ALS or provide approaches for possible therapeutic options.
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| 17. |
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| 18. |
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| 19. |
- Gromicho, Marta, et al.
(författare)
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Motor neuron disease beginning with frontotemporal dementia : clinical features and progression
- 2021
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 22:7-8, s. 508-516
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study disease characteristics, progression and outcome in a group of motor neuron disease (MND) patients beginning with frontotemporal dementia (FTD) by comparing them with patients with the typical motor-onset.Methods: 849 patients recruited from tertiary centers were studied according to FTD-onset and motor-onset. We studied clinical data, functional decline and survival.Results: Twenty six patients (3.1%) had FTD-onset of whom seven (26.9%) had coincident motor dysfunction. In those with isolated FTD-onset, motor symptoms developed after a median of 12 months (IQR: 4-18). FTD-onset patients were older at presentation; the bulbar-region was more frequently first affected than in the motor-onset group; there was a predominant upper motor neuron (UMN) phenotype; fasciculations were less common than in motor onset disease but facial and upper limb apraxia was more frequent; as well as ALS and FTD familial history. No differences were observed for gender, frequency of C9orf72 hexanucleotide repeat expansion, family history of Alzheimer's and Parkinson's diseases, median delay from motor symptoms to diagnosis, median ALSFRS-R rate of change, handedness, emotional lability, depression, weight loss, resting tremor, bradykinesia, sensory changes or neuropathy. Clinical and demographic features were similar between FTD-onset patients developing bulbar MND and bulbar-onset ALS patients. Once bulbar symptoms manifested functional progression and survival were similar to those of bulbar-onset ALS patients.Conclusions: MND patients with FTD-onset have a distinctive phenotype characterized by predominant UMN presentation and rapid progression to bulbar involvement. The main factor impacting functional decline and survival is the onset of bulbar dysfunction.
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| 20. |
- Gudmundsdottir, Valborg, et al.
(författare)
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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes : an IMI-DIRECT study
- 2020
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Ingår i: Genome Medicine. - : BioMed Central. - 1756-994X .- 1756-994X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
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