| 1. |
- Månberg, Anna, 1985-, et al.
(författare)
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Altered perivascular fibroblast activity precedes ALS disease onset
- 2021
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Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 27:4, s. 640-646
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Tidskriftsartikel (refereegranskat)abstract
- Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
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| 2. |
- Al-Chalabi, Ammar, et al.
(författare)
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July 2017 ENCALS statement on edaravone
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : TAYLOR & FRANCIS LTD. - 2167-8421 .- 2167-9223. ; 18:7-8, s. 471-474
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Tidskriftsartikel (refereegranskat)abstract
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| 3. |
- Corcia, Philippe, et al.
(författare)
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Homozygous SMN2 deletion is a protective factor in the Swedish ALS population
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:5, s. 588-591
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations. European Journal of Human Genetics (2012) 20, 588-591; doi:10.1038/ejhg.2011.255; published online 25 January 2012
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| 4. |
- Couthouis, Julien, et al.
(författare)
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A yeast functional screen predicts new candidate ALS disease genes
- 2011
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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. ; 108:52, s. 20881-20890
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
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| 5. |
- Fang, Fang, et al.
(författare)
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Amyotrophic lateral sclerosis among cross-country skiers in Sweden.
- 2016
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 31:3, s. 247-253
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Tidskriftsartikel (refereegranskat)abstract
- A highly increased risk of amyotrophic lateral sclerosis (ALS) has been suggested among professional athletes. We aimed to examine whether long distance cross-country skiers have also a higher risk of ALS and whether the increased risk was modified by skiing performance. We followed 212,246 cross-country skiers in the Swedish Vasaloppet cohort and a random selection of 508,176 general Swedes not participating in the Vasaloppet during 1989-2010. The associations between cross-country skiing as well as skiing performance (i.e., type of race, finishing time and number of races) and the consequent risk of ALS were estimated through hazard ratios (HRs) derived from Cox model. During the study, 39 cases of ALS were ascertained among the skiers. The fastest skiers (100-150 % of winner time) had more than fourfold risk of ALS (HR 4.31, 95 % confidence interval [CI] 1.78-10.4), as compared to skiers that finished at >180 % of winner time. Skiers who participated >4 races during this period had also a higher risk (HR 3.13, 95 % CI 1.37-7.17) than those participated only one race. When compared to the non-skiers, the fastest skiers still had a higher risk (HR 2.08, 95 % CI 1.12-3.84), as skiers who had >4 races (HR 1.88, 95 % CI 1.05-3.35), but those finishing at >180 % of winner time had a lower risk (HR 0.46, 95 % CI 0.24-0.87). In conclusion, long distance cross-country skiing is associated with a higher risk of ALS, but only among the best skiers; recreational skiers appear to have a largely reduced risk.
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| 6. |
- Foucher, Juliette, et al.
(författare)
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Validity and reliability measures of the Swedish Karolinska version of the Edinburgh Cognitive and Behavioral ALS Screen (SK-ECAS)
- 2023
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 24:7-8, s. 713-718
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cognitive and behavioral impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a 5-domain screening tool customized for quick cognitive screening in patients with ALS. Although the ECAS is available in Swedish at the Karolinska University Hospital (SK-ECAS), it has not yet been validated in Sweden stressing the need to assess validity and reliability of the SK-ECAS Version A.Methods: The study included 176 patients with ALS or other motor neuron disease diagnosed between September 2017 and October 2021 at the Karolinska ALS Clinical Research Center in Stockholm, Sweden, and 35 age-matched healthy control subjects. SK-ECAS was validated against the Montreal Cognitive Assessment (MoCA) and optimal cutoffs, receiver operating characteristic (ROC) curve and area under the curve (AUC) were calculated.Results: We identified an optimal cutoff of 108 for the SK-ECAS total score and 82 for the SK-ECAS ALS-specific score to detect cognitive impairment. The SK-ECAS showed good performance in indicating abnormal cognition with an AUC of 0.73 for SK-ECAS ALS-specific score and 0.77 for SK-ECAS total score. There was good internal consistency with a Cronbach’s alpha of 0.79.Conclusions: This study demonstrates good validity and reliability indices for SK-ECAS Version A for the detection of cognitive impairment in newly diagnosed ALS patients.
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| 7. |
- Imrell, Sofia, 1985-, et al.
(författare)
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Increased incidence of motor neuron disease in Sweden : a population-based study during 2002-2021
- 2024
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Ingår i: Journal of Neurology. - : Springer. - 0340-5354 .- 1432-1459. ; 271:5, s. 2730-2735
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Motor neuron diseases (MND), with amyotrophic lateral sclerosis constituting most cases, are rare conditions of unknown etiology. There have been reports of an increase in incidence during the latter half of the twentieth century in various Western countries, including Sweden. This study provides updated data on the incidence of MND in Sweden during the last 20 years.METHODS: Data was obtained from the Swedish National Patient Register on individuals diagnosed with MND from 2002 to 2021 and analysed in relation to group level data for the entire Swedish population. Incidence rates were calculated and presented in relation to year, age, sex, and region.RESULTS: In the early 2000s, there was a crude incidence rate of 3.5-3.7 per 100,000 person-years, which then increased to 4.0-4.6 from 2008 onward. Age standardization to the starting year (2002) partially mitigated this increase. The incidence rate was greater among men compared to women and was highest within the age range of 70 to 84 years. There were indications of a higher incidence rate in the northernmost parts of the country, although the difference was not statistically significant.CONCLUSIONS: The incidence rate of MND in Sweden now seems to have surpassed 4 cases per 100,000 person-years. This is higher when compared to both other European countries and previous Swedish studies. It remains to be determined if this increase reflects an actual increasing incidence of MND in Sweden or is due to other factors such as better registry coverage.
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| 8. |
- Ingre, Caroline, et al.
(författare)
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A 50bp deletion in the SOD1 promoter lowers enzyme expression but is not associated with ALS in Sweden
- 2016
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa UK Limited. - 2167-8421 .- 2167-9223. ; 17:5-6, s. 452-457
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). A 50 base pair (bp) deletion of SOD1 has been suggested to reduce transcription and to be associated with later disease onset in ALS. This study was aimed to reveal if the 50bp deletion influenced SOD1 enzymatic activity, occurrence and phenotype of the disease in a Swedish ALS/control cohort. Blood samples from 512 Swedish ALS patients and 354 Swedish controls without coding SOD1 mutations were analysed for the 50bp deletion allele. The enzymatic activity of SOD1 in erythrocytes was analysed and genotype-phenotype correlations were assessed. Results demonstrated that the genotype frequencies of the 50bp deletion were all found to be in Hardy-Weinberg equilibrium. No significant differences were found for age of onset, disease duration or site of onset. SOD1 enzymatic activity showed a statistically significant decreasing trend in the control group, in which the allele was associated with a 5% reduction in SOD1 activity. The results suggest that the 50bp deletion has a moderate reducing effect on SOD1 synthesis. No modulating effects, however, were found on ALS onset, phenotype and survival in the Swedish population.
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| 9. |
- Ingre, Caroline, 1977-, et al.
(författare)
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A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts
- 2013
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Ingår i: Neurobiology of Aging. - New York : Elsevier. - 0197-4580 .- 1558-1497. ; 34:6
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Tidskriftsartikel (refereegranskat)abstract
- Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have veryrecently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, weperformed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporaldementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenicrelevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United Stateswere screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. Ina German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which wasabsent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recentlydescribed p.Gln117Gly sequence variant was found in another familial ALS patient from the United States.The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overtcognitive involvement. PFN1 mutations were absent in patients with motor neuron disease anddementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can causeALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the“classic” ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proofof-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motorneuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization byphosphorylation of profilin 1 might be necessary for motor neuron survival.
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| 10. |
- Ingre, Caroline, 1977-, et al.
(författare)
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Erythrocyte SOD1 enzyme activity in ALS patients is not modulated by a 50 bp deletion in the alleged SOD1 promotor
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background A known cause of ALS are mutations in the SOD1 gene. There is also evidence that SOD1 may be involved in cases lacking mutations in the gene. A 50 bp deletion located 1684 bp upstream of the start codon of SOD1 has been suggested to reduce transcription of SOD1, affect enzymatic activity and to be associated with later disease onset in ALS patients. The findings have been challenged by a study of Italian ALS patients, and here we examined the 50 bp deletion in Swedish ALS patients and controls. Methods Blood samples from 543 Swedish ALS patients and 356 Swedish controls were analysed for the 50 bp deletion and for SOD1 enzymic activity. The results were related to the disease phenotype of the patients.Results The frequency of the 50 bp deletion was the same in the patient and control cohorts, and both were found to be in Hardy-Weinberg equilibrium regarding the deletion. In relation to the different genotypes, no differences were detected in SOD1 enzymic activity, duration of disease, age of onset or site of onset.Conclusions When interpreting the present results together with previous results from other populations, we find it unlikely that the 50 bp deletion region has any regulatory function for the SOD1 gene, nor any effects on the phenotype of ALS.
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| 11. |
- Ingre, Caroline, et al.
(författare)
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Lipids, apolipoproteins, and prognosis of amyotrophic lateral sclerosis
- 2020
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Ingår i: Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1526-632X.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether lipids and apolipoproteins predict prognosis of patients with amyo- trophic lateral sclerosis in a cohort study of 99 patients with amyotrophic lateral sclerosis who were diagnosed during 2015 to 2018 and followed up until October 31, 2018, at the Neurology Clinic in Karolinska University Hospital in Stockholm, Sweden. Methods: Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein AI, apolipoprotein B, and lipid ratios were measured at the time of amyotrophic lateral sclerosis diagnosis or shortly thereafter. Death after amyotrophic lateral sclerosis diagnosis was used as the main outcome. The Cox model was used to estimate hazard ratios with 95% confidence intervals of death after amyotrophic lateral sclerosis diagnosis, after controlling for sex, age at diagnosis, site of symptom onset, diagnostic delay, body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score, and progression rate. Results: A 1-SD increase of total cholesterol (hazard ratio 0.60, 95% confidence interval 0.41–0.89, p = 0.01), low-density lipoprotein cholesterol (hazard ratio 0.64, 95% confidence interval 0.44–0.92, p = 0.02), low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (hazard ratio 0.65, 95% confidence interval 0.46–0.92, p = 0.02), apolipoprotein B (hazard ratio 0.62, 95% confidence interval 0.44–0.88, p = 0.01), or apolipoprotein B/apolipoprotein AI ratio (hazard ratio 0.61, 95% confidence interval 0.43–0.86, p < 0.01) was associated with a lower risk of death after amyotrophic lateral sclerosis diagnosis. A dose-response relationship was also noted when these biomarkers were analyzed as categorical variables. Conclusions: Lipids and apolipoproteins are important prognostic indicators for amyotrophic lateral sclerosis and should be monitored at the diagnosis of amyotrophic lateral sclerosis.
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| 12. |
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| 13. |
- Ingre, Caroline, 1977-, et al.
(författare)
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No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland
- 2013
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Ingår i: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION. - : Informa Healthcare. - 2167-8421 .- 2167-9223. ; 14:7-8, s. 620-627
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Tidskriftsartikel (refereegranskat)abstract
- Linkage analysis in Brazilian families with amyotrophic lateral sclerosis (ALS) revealed that a missense mutation p. Pro56Ser in a conserved gene VAMP-associated protein type B and C (VAPB) cosegregates with disease. Blood samples were studied from 973 Swedish, 126 Portuguese and 19 Icelandic ALS patients, and from 644 control subjects. We identified five VAPB mutations, two of which are novel, in 14 Swedish ALS patients and in nine control individuals from Sweden and Portugal. The 14 patients with VAPB mutations all carried a diagnosis of sporadic ALS. Mutations were also found in healthy adult relatives. The p. Asp130Glu VAPB mutation was also found in two patients from an Icelandic ALS family, but the mutation did not cosegregate with disease. All patients were instead found to be heterozygous for a p.Gly93Ser SOD1 mutation. There were no clinical differences between them, suggesting that the p. Asp130Glu VAPB mutation is unrelated to the disease process. less thanbrgreater than less thanbrgreater thanIn conclusion, the VAPB mutations were as frequent in control individuals as in patients. This observation, in combination with the finding of several healthy relatives carrying the VAPB mutations and no ancestors with ALS disease, suggests that it is unlikely that these VAPB mutations are pathogenic.
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| 14. |
- Ingre, Caroline, 1977-
(författare)
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On the aetiology of ALS : a comprehensive genetic study
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Amyotrophic lateral sclerosis (ALS) is a deadly, progressive neuromuscular disease that affects individuals all over the world. About 10% of the patients have a familial predisposition (FALS) while the remainder of cases are isolated or sporadic (SALS) and of unknown cause. To date, the principal recognized risk factors for ALS are higher age, male gender, slim figure (BMI<23) and a family history of ALS. In 1993, Rosen et al. observed that some FALS cases were associated with mutations in the gene encoding the CuZn superoxide dismutase enzyme (SOD1). Since then, several mutations in the SOD1 gene have been discovered, and mutations in more than 18 other genes have been associated with causing ALS. The aim of this thesis was to identify new mutations associated with ALS pathogenesis, and by comparing patients from different countries, were we also able to identify population-specific genetic variations. The studies are referred to as I–V.Methods: With written informed consent and adhering to the tenets of the Declaration of Helsinki, through a national network of ALS clinicians´, venous blood samples were collected from ALS patients and healthy subjects in Europe and the USA. The patients were diagnosed according to the El Escorial criteria, and as having FALS according to the criteria of Byrne et al. (2011). The DNA variations were amplified by various PCR techniques. (I, III and IV) The amplicons of ataxin 2 (ATXN2), profilin 1 (PFN1), and vesicle-associated membrane protein type B (VAPB) were characterised by direct sequencing. (II) After quantitative PCR, a genotype-phenotype correlation was performed to assess whether the survival motor neuron gene (SMN) modulates the phenotype of ALS. (V) The amplicons of the 50 base pair deletion in the SOD1 promotor (50 bp) were separated by electrophoresis on agarose.Results: (I) We observed a significant association between CAG expansions in the ATXN2 gene and ALS in a European cohort. (II) Abnormal copy number of the SMN1 gene was identified as a risk factor in France, but not in Sweden. Homozygosity of the SMN2 deletion prolonged survival among Swedish ALS patients, compared to French patients. (III) We identified two mutations in the PFN1 gene, the novel p.Thr109Met mutation and the p.Gln117Gly mutation, in two unrelated FALS patients. (IV) In our cohort, we identified five VAPB mutations p.Asp130Glu, p.Ser160del, p.Asp162Glu, p.Met170Ile, and p.Arg184Trp, two of which are novel. (V) The 50 bp deletion upstream of the SOD1 gene was found in equal frequencies in both the patient and control cohorts. The 50 bp deletion did not affect SOD1 enzymatic activity. Furthermore, we found no differences in age of onset or disease duration in relation to the 50 bp deletion genotype.VIConclusions: (I) Our findings indicate that ATXN2 plays an important role in the pathogenesis of ALS, and that CAG expansions in ATXN2 are a significant risk factor for the disease. (II) We suggest that abnormal SMN1 gene copynumber cannot be considered a universal genetic susceptibility factor for ALS. We also propose that the effect of abnormal SMN2 gene copy number on ALS phenotype may differ between populations. (III) This work provides evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. The novel p.Thr109Met mutation also shows that disturbance of actin dynamics can cause motor neuron degeneration. (IV) We find it unlikely that the VAPB mutations cause ALS in our cohorts. (V) We find it unlikely that the 50 bp region contains important regulatory elements for SOD1 expression. This thesis supports the theory that ALS is a multigenetic disease, but there appears to be great genetic variation among apparently identical populations. These studies emphasise the importance of continuous genetic screening, to identify further mutations and genes involved in ALS disease, but it also highlights the importance of cooperation and comparison between countries.
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| 15. |
- Kamal, Habiba, et al.
(författare)
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The cascade of care for patients with chronic hepatitis delta in Southern Stockholm, Sweden for the past 30 years
- 2024
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Ingår i: Liver international. - : Wiley-Blackwell Publishing Inc.. - 1478-3223 .- 1478-3231. ; 44:1, s. 228-240
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden.METHODS: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression.RESULTS: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6).CONCLUSION: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis.
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| 16. |
- Kliest, Tessa, et al.
(författare)
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Clinical trials in pediatric ALS: a TRICALS feasibility study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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| 17. |
- Kläppe, Ulf, et al.
(författare)
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Mortality among family members of patients with amyotrophic lateral sclerosis : a Swedish register-based study
- 2022
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa Healthcare. - 2167-8421 .- 2167-9223. ; 23:3-4, s. 226-235
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test two hypotheses: (1) partners of ALS patients have higher mortality due to outcomes related to psychological distress, and (2) parents and siblings of ALS patients have higher mortality due to diseases that co-occur with ALS.Methods: We performed a nationwide, register-based cohort study in Sweden. We included ALS-free partners, biological parents and full siblings (N = 11,704) of ALS patients, as well as ALS-free partners, biological parents and full siblings (N = 14,460,150) of ALS-free individuals, and followed them during 1961-2013. Hazard ratios (HRs) and 95% confidence intervals (CIs) of overall and cause-specific mortality were derived from Cox regression.Results: Partners of ALS patients, compared to partners of ALS-free individuals, displayed higher mortality due to external causes (HR 2.14; 95% CI 1.35-3.41), including suicide (HR 2.44; 95% CI 1.09-5.44) and accidents (HR 2.09; 95% CI 1.12-3.90), after diagnosis of the ALS patients. Parents of ALS patients had a slightly higher overall mortality (HR 1.03; 95% CI 1.00-1.07), compared with parents of ALS-free individuals. This was driven by mortality due to dementias and cardiovascular, respiratory, and skin diseases. Parents of ALS patients had, however, lower mortality than parents of ALS-free individuals due to neoplasms. Siblings of ALS patients had higher mortality due to dementias, and digestive and skin diseases.Conclusions: Increased mortality due to suicide and accidents among partners of ALS patients is likely attributable to severe psychological distress following the ALS diagnosis. Increased mortality due to dementias among parents and full siblings of ALS patients suggests shared mechanisms between neurodegenerative diseases.
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| 18. |
- Kläppe, Ulf, et al.
(författare)
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Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.
- 2023
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Ingår i: Amyotrophic lateral sclerosis & frontotemporal degeneration. - 2167-9223. ; 25:1-2, s. 150-61
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Tidskriftsartikel (refereegranskat)abstract
- To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS).This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time.Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients.Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time.
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| 19. |
- 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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| 20. |
- Longinetti, Elisa, et al.
(författare)
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Neurodegenerative and psychiatric diseases among families with amyotrophic lateral sclerosis
- 2017
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Ingår i: Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0028-3878 .- 1526-632X. ; 89:6, s. 578-585
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families. Methods: We conducted a register-based nested case-control study during 1990-2013 in Sweden to assess whether ALS patients had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 ALS patients and 36,480 age-, sex-, and county-of-birth matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of ALS patients and their controls. Results: Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio=1.49, 95% confidence interval=1.35-1.66), compared to individuals without these diseases. After diagnosis, ALS patients had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio=2.90, 95% confidence interval=2.46-3.43), compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson’s disease, other dementia, Alzheimer’s disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of ALS patients had higher risk of neurodegenerative diseases, whereas only children of ALS patients had higher risk of psychiatric disorders, compared to relatives of the controls. Conclusions: Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among ALS patients and their children might be attributable to non-motor symptoms of ALS and severe stress response toward the diagnosis.
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| 21. |
- Longinetti, Elisa, et al.
(författare)
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The Swedish motor neuron disease quality registry
- 2018
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 19:7-8, s. 528-537
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We set up the Swedish Motor Neuron Disease (MND) Quality Registry to assure early diagnosis and high-quality health care for all MND patients (mainly amyotrophic lateral sclerosis, ALS), and to create a research base by prospectively following the entire MND population in Sweden. Methods: Since 2015, the MND Quality Registry continuously collects information about a wide range of clinical measures, biological samples, and quality of life outcomes from all MND patients recruited at the time of MND diagnosis in Sweden and followed at each clinic visit approximately every 12 weeks. The Registry includes an Internet based patient own reporting portal that involves patients in the registration of their current symptoms and health status. Results: As of 20th January 2017, the MND Quality Registry included 99% of the MND patients of the Stockholm area (N = 194), consisting mostly of ALS patients (N = 153, 78.9%), followed by patients labeled as MND due to a neurophysiology finding but not fulfilling the criteria for ALS (N = 20, 10.3%), primary lateral sclerosis (N = 13, 6.7%), and progressive spinal muscular atrophy patients (N = 8, 4.1%). A higher proportion of these patients were women (N = 100, 52%), and women and men had a similar age at symptoms onset (59 years). Conclusions: Main strengths of the MND Quality Registry are its clinical, quantitative, qualitative, and prospective nature, providing the researchers potential means of identifying appropriate candidates for clinical trials and other research projects, as well as assuring to the patients an effective and adequate time spent on-site with the healthcare professionals.
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| 22. |
- McKay, Kyla A, et al.
(författare)
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Military service and related risk factors for amyotrophic lateral sclerosis.
- 2021
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Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 143:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- The cause of amyotrophic lateral sclerosis (ALS) is unknown, but occupations have been explored as a potential proxy measure of risk. There is a substantial body of literature connecting military service to ALS. We aimed to summarize and assess the quality of this evidence.Systematic review of the literature, including observational studies which explored one of the following exposures: general military service (army, air force, marines, or navy); or specific exposures associated with military service measured amongst military personnel. The outcome of interest was ALS incidence, which could include onset, diagnosis, or death from ALS.A total of 2642 articles were screened. Following exclusion, 19 articles remained for inclusion in the systematic review, including 1 meta-analysis and 18 original observational studies. Most studies were of moderate quality. In general, the relationship between military service was suggestive of an increased risk, particularly among Gulf War and WWII veterans. Exposure to pesticides (including Agent Orange) certain chemicals (exhaust, burning agents), heavy metals, and head trauma, appeared to increase the risk of ALS among military personnel.There is a possible association between military service and the subsequent development of ALS; however, the evidence was limited. Studies were generally hindered by small sample sizes and inadequate follow-up time. Future studies should endeavour to objectively measure specific exposures, or combinations thereof, associated with military service, as this will be of vital importance in implementing preventative strategies into military organisations.
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| 23. |
- Sun, Jiangwei, et al.
(författare)
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Antibiotics Use and Risk of Amyotrophic Lateral Sclerosis in Sweden
- 2019
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Ingår i: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 26:11, s. 1355-1361
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Previous animal studies have suggested disrupted intestinal microbiome in amyotrophic lateral sclerosis (ALS). Due to the known effect of antibiotics on gut microflora, the potential role of antibiotics use on the risk of ALS deserves an investigation.METHODS: A nested case-control study was conducted using several Swedish national registers. We included 2,484 ALS patients diagnosed between July 1, 2006 and December 31, 2013 as cases and randomly selected five controls per case who were individually matched to the case by sex, birth year, and area of residence from the general Swedish population. Information on antibiotics prescriptions before ALS diagnosis was extracted from the Prescribed Drug Register for both cases and controls. Conditional logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).RESULTS: After accounting for potential diagnostic delay in ALS by excluding all prescriptions within one year before diagnosis, any antibiotics use was associated with a higher risk of ALS. The ORs (95% CIs) were 1.06 (0.94-1.19), 1.13 (1.00-1.28), and 1.18 (1.03-1.35) when comparing one, 2-3, and ≥4 prescriptions to no prescription (P for trend = 0.0069). Similar results were noted for antibiotics used for respiratory infections and urinary tract as well as skin and soft tissue infections. Among different individual antibiotics, the risk of ALS was especially increased in relation to more than two prescriptions of beta-lactamase sensitive penicillin (OR=1.28; 95% CI 1.10-1.50).CONCLUSIONS: Use of antibiotics, especially repeated, might be associated with a higher subsequent risk of ALS.
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| 24. |
- Sun, Jiangwei, et al.
(författare)
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Hospital-treated infections in early- and mid-life and risk of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis : A nationwide nested case-control study in Sweden
- 2022
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Ingår i: PLoS Medicine. - : Public Library of Science. - 1549-1277 .- 1549-1676. ; 19:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Experimental observations have suggested a role of infection in the etiology of neurodegenerative disease. In human studies, however, it is difficult to disentangle whether infection is a risk factor or rather a comorbidity or secondary event of neurodegenerative disease. To this end, we examined the risk of 3 most common neurodegenerative diseases in relation to previous inpatient or outpatient episodes of hospital-treated infections.Methods and findings: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) during 1970 to 2016 in Sweden, identified from the National Patient Register. For each case, 5 controls individually matched to the case on sex and year of birth were randomly selected from the general population. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for potential confounders, including sex, year of birth, area of residence, educational attainment, family history of neurodegenerative disease, and Charlson comorbidity index. Infections experienced within 5 years before diagnosis of neurodegenerative disease were excluded to reduce the influence of surveillance bias and reverse causation. The analysis included 291,941 AD cases (median age at diagnosis: 76.2 years; male: 46.6%), 103,919 PD cases (74.3; 55.1%), and 10,161 ALS cases (69.3; 56.8%). A hospital-treated infection 5 or more years earlier was associated with an increased risk of AD (OR = 1.16, 95% CI: 1.15 to 1.18, P < 0.001) and PD (OR = 1.04, 95% CI: 1.02 to 1.06, P < 0.001). Similar results were observed for bacterial, viral, and other infections and among different sites of infection including gastrointestinal and genitourinary infections. Multiple infections before age 40 conveyed the greatest risk of AD (OR = 2.62, 95% CI: 2.52 to 2.72, P < 0.001) and PD (OR = 1.41, 95% CI: 1.29 to 1.53, P < 0.001). The associations were primarily due to AD and PD diagnosed before 60 years (OR = 1.93, 95% CI: 1.89 to 1.98 for AD, P < 0.001; OR = 1.29, 95% CI: 1.22 to 1.36 for PD, P < 0.001), whereas no association was found for those diagnosed at 60 years or older (OR = 1.00, 95% CI: 0.98 to 1.01 for AD, P = 0.508; OR = 1.01, 95% CI: 0.99 to 1.03 for PD, P = 0.382). No association was observed for ALS (OR = 0.97, 95% CI: 0.92 to 1.03, P = 0.384), regardless of age at diagnosis. Excluding infections experienced within 10 years before diagnosis of neurodegenerative disease confirmed these findings. Study limitations include the potential misclassification of hospital-treated infections and neurodegenerative diseases due to incomplete coverage of the National Patient Register, as well as the residual confounding from unmeasured risk or protective factors for neurodegenerative diseases.Conclusions: Hospital-treated infections, especially in early- and mid-life, were associated with an increased risk of AD and PD, primarily among AD and PD cases diagnosed before 60 years. These findings suggest that infectious events may be a trigger or amplifier of a preexisting disease process, leading to clinical onset of neurodegenerative disease at a relatively early age. However, due to the observational nature of the study, these results do not formally prove a causal link.
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