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| 2. |
- van Rheenen, W, et al.
(författare)
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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
- 2021
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 53:12, s. 1636-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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| 3. |
- Kuraszkiewicz, B., et al.
(författare)
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Potential Preventive Strategies for Amyotrophic Lateral Sclerosis
- 2020
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 14
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Forskningsöversikt (refereegranskat)abstract
- It may seem useless to propose preventive measures for a disease without established pathogenesis and successful therapy, such as amyotrophic lateral sclerosis (ALS). However, we will show that ALS shares essential molecular mechanisms with aging and that established anti-aging strategies, such as healthy diet or individually adjusted exercise, may be successfully applied to ameliorate the condition of ALS patients. These strategies might be applied for prevention if persons at ALS risk could be identified early enough. Recent research advances indicate that this may happen soon.
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| 4. |
- Pinto, Susana, et al.
(författare)
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Impact of diabetes mellitus on the respiratory function of amyotrophic lateral sclerosis patients
- 2024
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Ingår i: European Journal of Neurology. - 1351-5101. ; 31:2
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain.Methods: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t-test, chi(2), or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan-Meier analysis assessed survival. p < 0.05 was considered significant.Results: We included 1639 patients (922 men, mean onset age = 62.5 +/- 12.6 years, mean disease duration = 18.1 +/- 22.0 months). Mean survival was 43.3 +/- 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS-R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2mean (p = 0.014).Conclusions: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.
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| 5. |
- De Carvalho, Mamede, et al.
(författare)
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International Survey of ALS Experts about Critical Questions for Assessing Patients with ALS
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 505-510
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To define an applicable dataset for ALS patient registries we weighted specific clinical items as scored by worldwide ALS experts.Methods: Sixty participants were invited based on relevant clinical work, publications and personal acquaintance. They rated 160 clinical items consensually agreed by the members of our project, incorporating specialists from five European Centres. Scoring scheme was defined as: 1 - essential; 2 - important; 3 - not very important. A mixed effect model was applied to rank items and to find possible correlations with geographical region (Europe vs. outside Europe).Results: We received 40 responses, 20 from Europe and 20 from outside; 42/160 data were scored as essential by >50% of the respondents, including: date of birth, gender, date of disease onset, date of diagnosis, ethnicity, region of onset, predominant upper neuron (UMN) or lower motor neuron (LMN) impairment, proximal versus distal weakness, respiratory symptoms, dysarthria, weight loss, signs of LMN/UMN involvement, emotional incontinence, cognitive changes, respiratory signs, neck weakness, body mass index, ALSFRS-R at entry, ALSFRS-R subscores at entry, timing and pattern of spreading and staging, electromyography, spirometry, MRI, CK level, riluzole intake, genetic background, history of physical exercise and previous and current main occupation. Four components were scored as non-relevant, including place of birth, blood pressure and pain at onset. There was no significant difference between regions (European vs. non-European countries).Conclusions: Our study identified a consensual set of clinical data with 42 specific items that can be used as a minimal data set for patient registers and for clinical trials.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Gromicho, Marta, et al.
(författare)
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Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis
- 2018
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS) erelated genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p. Ala152Pro (c. 457G>C). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations incidence in ALS patients (w10%) and associated phenotypes suggest that genetic tests should be offered to more patients, and other genes should be investigated in our population.
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| 9. |
- 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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| 10. |
- Korner, Sonja, et al.
(författare)
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Influence of Environment and Lifestyle on Incidence and Progress of Amyotrophic Lateral Sclerosis in A German ALS Population
- 2019
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Ingår i: Aging and Disease. - Fort Worth : International Society on Aging & Disease. - 2152-5250. ; 10:2, s. 205-216
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly affecting upper and lower motor neurons in the brain and spinal cord. Pathogenesis of ALS is still unclear, and a multifactorial etiology is presumed. The remarkable clinical heterogeneity between different phenotypes of ALS patients suggests that environmental and lifestyle factors could play a role in onset and progression of ALS. We analyzed a cohort of 117 ALS patients and 93 controls. ALS patients and controls were compared regarding physical activity, dietary habits, smoking, residential environment, potentially toxic environmental factors and profession before symptom onset and throughout the disease course. Data were collected by a personal interview. For statistical analysis descriptive statistics, statistical tests and analysis of variance were used. ALS patients and controls did not differ regarding smoking, diet and extent of physical training. No higher frequency of toxic influences could be detected in the ALS group. ALS patients lived in rural environment considerably more often than the control persons, but this was not associated with a higher percentage of occupation in agriculture. There was also a higher percentage of university graduates in the ALS group. Patients with bulbar onset were considerably more often born in an urban environment as compared to spinal onset. Apart from education and environment, ALS phenotypes did not differ in any investigated environmental or life-style factor. The rate of disease progression was not influenced by any of the investigated environmental and life-style factors. The present study could not identify any dietary habit, smoking, physical activity, occupational factor as well as toxic influences as risk factor or protective factor for onset or progression of ALS. Living in rural environment and higher education might be associated with higher incidence of ALS.
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