Pub Date : 2017-04-03DOI: 10.1080/21678421.2016.1223141
A. Esquinas, G. Garuti, G. Pellegrino, G. S. Sferrazza Papa
Poor prognosis in amyotrophic lateral sclerosis (ALS) is primarily caused by the development of acute respiratory failure (ARF). Despite the recent proposal of a scoring system for early prediction of patient survival (1), this remains challenging due to the clinical heterogeneity of the disease. Non-invasive ventilation (NIV) may counterbalance the progression of ARF; however, the optimal strategies for applying NIV, including patient selection and timing, remain controversial (2). On this issue, we read with interest the article by N. Gonzalez Calzada et al., which focused on defining potential survival factors in ALS (3). In a large cohort of ALS patients, the author confirmed that the severity of bulbar involvement and the ALSFRS-R score at the time of NIV initiation strongly predict patient survival. A key topic in assessing patient survival is the definition of survival time as time to death or to tracheostomy. We think that the clinical protocol used by the authors to propose tracheostomy and invasive mechanical ventilation, and the percentage of patients in which it was performed, should be reported and discussed in the letter. We agree with the authors that a better assessment of bulbar involvement, including evaluation of the upper airways, and a careful titration of NIV are necessary to improve the efficacy of the treatment. However, we would like to point out an important unresolved issue, which is how respiratory evaluation should be performed. Respiratory symptoms may be under-perceived and arterial blood gas analysis usually begins to alter only late in the progression of the disease. Authors have considered spirometry with the generally accepted cut-off of forced vital capacity (FVC) of less than 50% of the predicted value as the threshold to start NIV. In spite of this, spirometry remains the reference test to assess overall ventilatory function; in this cohort a valid spirometry was available only for half to onethird of patients with moderate to severe bulbar dysfunction. Thus, this cohort highlights a gap in evaluating respiratory function in patients with advanced disease. If it is true that pulmonary function tests are affected by diaphragmatic dysfunction as shown by a decrease in vital capacity, due to the non-linear relationship between lung volume and muscle force, the decrease in lung volumes occurs relatively late compared to the development of muscle dysfunction. Moreover, spirometry requires patient cooperation and may not be reliable in the presence of facial weakness and mouth leaks during forced manoeuvre, which is frequently the case with ALS patients. Performing the test becomes more challenging in patients with bulbar dysfunction who tend to rapidly progress towards ARF and, thus, would require frequent monitoring. Sleep studies may help show nocturnal desaturation. However, what it is needed is a test focused on measuring respiratory muscles. Ultrasonography is a non-invasive, non-ionizing imaging technique th
{"title":"Survival in amyotrophic lateral sclerosis patients on non-invasive ventilation. What can we do more?","authors":"A. Esquinas, G. Garuti, G. Pellegrino, G. S. Sferrazza Papa","doi":"10.1080/21678421.2016.1223141","DOIUrl":"https://doi.org/10.1080/21678421.2016.1223141","url":null,"abstract":"Poor prognosis in amyotrophic lateral sclerosis (ALS) is primarily caused by the development of acute respiratory failure (ARF). Despite the recent proposal of a scoring system for early prediction of patient survival (1), this remains challenging due to the clinical heterogeneity of the disease. Non-invasive ventilation (NIV) may counterbalance the progression of ARF; however, the optimal strategies for applying NIV, including patient selection and timing, remain controversial (2). On this issue, we read with interest the article by N. Gonzalez Calzada et al., which focused on defining potential survival factors in ALS (3). In a large cohort of ALS patients, the author confirmed that the severity of bulbar involvement and the ALSFRS-R score at the time of NIV initiation strongly predict patient survival. A key topic in assessing patient survival is the definition of survival time as time to death or to tracheostomy. We think that the clinical protocol used by the authors to propose tracheostomy and invasive mechanical ventilation, and the percentage of patients in which it was performed, should be reported and discussed in the letter. We agree with the authors that a better assessment of bulbar involvement, including evaluation of the upper airways, and a careful titration of NIV are necessary to improve the efficacy of the treatment. However, we would like to point out an important unresolved issue, which is how respiratory evaluation should be performed. Respiratory symptoms may be under-perceived and arterial blood gas analysis usually begins to alter only late in the progression of the disease. Authors have considered spirometry with the generally accepted cut-off of forced vital capacity (FVC) of less than 50% of the predicted value as the threshold to start NIV. In spite of this, spirometry remains the reference test to assess overall ventilatory function; in this cohort a valid spirometry was available only for half to onethird of patients with moderate to severe bulbar dysfunction. Thus, this cohort highlights a gap in evaluating respiratory function in patients with advanced disease. If it is true that pulmonary function tests are affected by diaphragmatic dysfunction as shown by a decrease in vital capacity, due to the non-linear relationship between lung volume and muscle force, the decrease in lung volumes occurs relatively late compared to the development of muscle dysfunction. Moreover, spirometry requires patient cooperation and may not be reliable in the presence of facial weakness and mouth leaks during forced manoeuvre, which is frequently the case with ALS patients. Performing the test becomes more challenging in patients with bulbar dysfunction who tend to rapidly progress towards ARF and, thus, would require frequent monitoring. Sleep studies may help show nocturnal desaturation. However, what it is needed is a test focused on measuring respiratory muscles. Ultrasonography is a non-invasive, non-ionizing imaging technique th","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1223141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47139475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-04-03DOI: 10.1080/21678421.2016.1262423
Angelica Nordin, C. Akimoto, Anna Wuolikainen, Helena Alstermark, K. Forsberg, P. Baumann, S. Pinto, M. de Carvalho, A. Hübers, Frida Nordin, A. Ludolph, Jochen H Weishaupt, T. Meyer, T. Grehl, K. Schweikert, Markus Weber, Christian Burkhardt, C. Neuwirth, T. Holmøy, M. Morita, O. Tysnes, M. Benatar, J. Wuu, D. Lange, C. Bisgård, N. Asgari, I. Tarvainen, T. Brännström, P. Andersen
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.
{"title":"Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study","authors":"Angelica Nordin, C. Akimoto, Anna Wuolikainen, Helena Alstermark, K. Forsberg, P. Baumann, S. Pinto, M. de Carvalho, A. Hübers, Frida Nordin, A. Ludolph, Jochen H Weishaupt, T. Meyer, T. Grehl, K. Schweikert, Markus Weber, Christian Burkhardt, C. Neuwirth, T. Holmøy, M. Morita, O. Tysnes, M. Benatar, J. Wuu, D. Lange, C. Bisgård, N. Asgari, I. Tarvainen, T. Brännström, P. Andersen","doi":"10.1080/21678421.2016.1262423","DOIUrl":"https://doi.org/10.1080/21678421.2016.1262423","url":null,"abstract":"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.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1262423","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42461226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-04-03DOI: 10.1080/21678421.2016.1249886
E. Pupillo, E. Bianchi, M. Poloni, E. Beghi
Abstract Objective: To revise the first diagnosis of amyotrophic lateral sclerosis (ALS) in patients from a well-defined population. Methods: Patients diagnosed with ALS in the years 1998-2002 and resident of Lombardy Region, Northern Italy were followed until death or April 30 2016 to assess long-term survival. During follow-up, the caring neurologists were asked to confirm the first diagnosis. Revised diagnoses were classified as confirmed and unconfirmed motor neuron disease (MND) with further specification where available. The two groups were compared for age, sex, disease duration at diagnosis, site of onset, and El Escorial category. Survival with predictors were also compared. Results: Included were 280 men and 203 women aged 18-93 years. During follow-up, 25 cases (5.2%) received a diagnosis different from MND. Diseases of spinal roots and peripheral nerves and vascular encephalopathy predominated. Patients with definite (OR 0.15; 95%CI 0.04-0.52) and probable (OR 0.15; 95%CI 0.04-0.62) ALS were least likely to have an unconfirmed MND diagnosis. At end of follow-up, 2.2% of patients with confirmed MND and 44.0% of patients with unconfirmed MND were reported alive (HR 0.14; 95%CI 0.08-0.25). Conclusions: At the time of a first diagnosis of ALS, the possibility still exists that another, less severe clinical condition, is present.
{"title":"Is firstly diagnosed ALS really ALS? Results of a population-based study with long-term follow-up","authors":"E. Pupillo, E. Bianchi, M. Poloni, E. Beghi","doi":"10.1080/21678421.2016.1249886","DOIUrl":"https://doi.org/10.1080/21678421.2016.1249886","url":null,"abstract":"Abstract Objective: To revise the first diagnosis of amyotrophic lateral sclerosis (ALS) in patients from a well-defined population. Methods: Patients diagnosed with ALS in the years 1998-2002 and resident of Lombardy Region, Northern Italy were followed until death or April 30 2016 to assess long-term survival. During follow-up, the caring neurologists were asked to confirm the first diagnosis. Revised diagnoses were classified as confirmed and unconfirmed motor neuron disease (MND) with further specification where available. The two groups were compared for age, sex, disease duration at diagnosis, site of onset, and El Escorial category. Survival with predictors were also compared. Results: Included were 280 men and 203 women aged 18-93 years. During follow-up, 25 cases (5.2%) received a diagnosis different from MND. Diseases of spinal roots and peripheral nerves and vascular encephalopathy predominated. Patients with definite (OR 0.15; 95%CI 0.04-0.52) and probable (OR 0.15; 95%CI 0.04-0.62) ALS were least likely to have an unconfirmed MND diagnosis. At end of follow-up, 2.2% of patients with confirmed MND and 44.0% of patients with unconfirmed MND were reported alive (HR 0.14; 95%CI 0.08-0.25). Conclusions: At the time of a first diagnosis of ALS, the possibility still exists that another, less severe clinical condition, is present.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1249886","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43596772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-04-03DOI: 10.1080/21678421.2016.1254245
G. Chadi, J. R. Maximino, F. Jorge, Fabrício Castro de Borba, J. M. Gilio, D. Callegaro, C. G. Lopes, Samantha Nakamura Dos Santos, G. Rebelo
Abstract Objective: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Methods: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Results: Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. Conclusions: TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.
{"title":"Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center","authors":"G. Chadi, J. R. Maximino, F. Jorge, Fabrício Castro de Borba, J. M. Gilio, D. Callegaro, C. G. Lopes, Samantha Nakamura Dos Santos, G. Rebelo","doi":"10.1080/21678421.2016.1254245","DOIUrl":"https://doi.org/10.1080/21678421.2016.1254245","url":null,"abstract":"Abstract Objective: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Methods: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Results: Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. Conclusions: TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1254245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46748939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-04-03DOI: 10.1080/21678421.2016.1245757
Joo-Yeon Engelen-Lee, A. Blokhuis, Wim G.M. Spliet, R. Pasterkamp, E. Aronica, Jeroen A. A. Demmers, R. Broekhuizen, Giovanni Nardo, N. Bovenschen, Leonard H. van den Berg
Abstract Background: We aimed to gain new insights into the pathogenesis of sporadic ALS (sALS) through a comprehensive proteomic analysis. Methods: Protein profiles of the anterior and posterior horn in post-mortem spinal cord samples of 10 ALS patients and 10 controls were analysed using 2D-differential gel electrophoresis. The identified protein spots with statistically significant level changes and a spot ratio >2.0 were analysed by LC-MS/MS. Results: In the posterior horn only 3 proteins were differentially expressed. In the anterior horn, 16 proteins with increased levels and 2 proteins with decreased levels were identified in ALS compared to controls. The identified proteins were involved in mitochondrial metabolism, calcium homeostasis, protein metabolism, glutathione homeostasis, protein transport and snRNP assembly. The two proteins with decreased levels, ATP5D and calmodulin, were validated by Western blot and immunostaining. Immunohistochemical and immunofluorescent double staining of ATP5D and synaptophysin showed that the reduction of ATP5D was most pronounced at synapses. Conclusions: We speculate that mitochondrial dysfunction in synaptic clefts could play an important role in sALS pathogenesis. A similar approach revealed decreased calmodulin expression mainly in the neuronal body and dendrites of ALS patients. These findings contribute to a deeper understanding of the disease process underlying ALS.
{"title":"Proteomic profiling of the spinal cord in ALS: decreased ATP5D levels suggest synaptic dysfunction in ALS pathogenesis","authors":"Joo-Yeon Engelen-Lee, A. Blokhuis, Wim G.M. Spliet, R. Pasterkamp, E. Aronica, Jeroen A. A. Demmers, R. Broekhuizen, Giovanni Nardo, N. Bovenschen, Leonard H. van den Berg","doi":"10.1080/21678421.2016.1245757","DOIUrl":"https://doi.org/10.1080/21678421.2016.1245757","url":null,"abstract":"Abstract Background: We aimed to gain new insights into the pathogenesis of sporadic ALS (sALS) through a comprehensive proteomic analysis. Methods: Protein profiles of the anterior and posterior horn in post-mortem spinal cord samples of 10 ALS patients and 10 controls were analysed using 2D-differential gel electrophoresis. The identified protein spots with statistically significant level changes and a spot ratio >2.0 were analysed by LC-MS/MS. Results: In the posterior horn only 3 proteins were differentially expressed. In the anterior horn, 16 proteins with increased levels and 2 proteins with decreased levels were identified in ALS compared to controls. The identified proteins were involved in mitochondrial metabolism, calcium homeostasis, protein metabolism, glutathione homeostasis, protein transport and snRNP assembly. The two proteins with decreased levels, ATP5D and calmodulin, were validated by Western blot and immunostaining. Immunohistochemical and immunofluorescent double staining of ATP5D and synaptophysin showed that the reduction of ATP5D was most pronounced at synapses. Conclusions: We speculate that mitochondrial dysfunction in synaptic clefts could play an important role in sALS pathogenesis. A similar approach revealed decreased calmodulin expression mainly in the neuronal body and dendrites of ALS patients. These findings contribute to a deeper understanding of the disease process underlying ALS.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1245757","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44726571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-02-06DOI: 10.1080/21678421.2017.1283418
Christian Burkhardt, C. Neuwirth, Markus Weber
Abstract Objective: The study objective was to assess whether controls and ALS patients show a practice effect in the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) on repeated longitudinal testing and if the ECAS detects progression of cognitive or behavioural changes over time. Methods: The ECAS was administered serially to ALS patients (n = 24 after six months, n = 10 after 12–18 months) and controls (n = 21 after six months). The ECAS was fully performed by all participants. For comparison purposes the Frontal Assessment Battery (FAB) was administered to a subgroup of 14 patients and 14 controls. Results: After six months controls showed a significantly higher overall score (p < 0.001) and significantly higher scores in all subdomains of the ECAS, except for visuospatial function and fluency. ALS patients showed no significant difference in any score of the ECAS after six months and up to18 months. Behavioural changes were increasingly, but not statistically, significant, noted by patient carers. The FAB was no longer applicable due to progressive motor deficits in 20% of ALS patients. Conclusions: In conclusion, in contrast to healthy controls, ALS patients show no practice effects. This could reflect ‘pre-symptomatic’ cognitive decline and progressive behavioural symptoms.
{"title":"Longitudinal assessment of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): lack of practice effect in ALS patients?","authors":"Christian Burkhardt, C. Neuwirth, Markus Weber","doi":"10.1080/21678421.2017.1283418","DOIUrl":"https://doi.org/10.1080/21678421.2017.1283418","url":null,"abstract":"Abstract Objective: The study objective was to assess whether controls and ALS patients show a practice effect in the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) on repeated longitudinal testing and if the ECAS detects progression of cognitive or behavioural changes over time. Methods: The ECAS was administered serially to ALS patients (n = 24 after six months, n = 10 after 12–18 months) and controls (n = 21 after six months). The ECAS was fully performed by all participants. For comparison purposes the Frontal Assessment Battery (FAB) was administered to a subgroup of 14 patients and 14 controls. Results: After six months controls showed a significantly higher overall score (p < 0.001) and significantly higher scores in all subdomains of the ECAS, except for visuospatial function and fluency. ALS patients showed no significant difference in any score of the ECAS after six months and up to18 months. Behavioural changes were increasingly, but not statistically, significant, noted by patient carers. The FAB was no longer applicable due to progressive motor deficits in 20% of ALS patients. Conclusions: In conclusion, in contrast to healthy controls, ALS patients show no practice effects. This could reflect ‘pre-symptomatic’ cognitive decline and progressive behavioural symptoms.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2017.1283418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48223263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-02-06DOI: 10.1080/21678421.2016.1259334
R. Sufit, S. Ajroud-Driss, Patricia Casey, J. Kessler
Abstract Objective: To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS). Methods: Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity. Results: Seventeen of 18 participants completed the study. All participants tolerated 64 mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression. Conclusions: Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.
{"title":"Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis","authors":"R. Sufit, S. Ajroud-Driss, Patricia Casey, J. Kessler","doi":"10.1080/21678421.2016.1259334","DOIUrl":"https://doi.org/10.1080/21678421.2016.1259334","url":null,"abstract":"Abstract Objective: To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS). Methods: Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity. Results: Seventeen of 18 participants completed the study. All participants tolerated 64 mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression. Conclusions: Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1259334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49585000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-02-02DOI: 10.1080/21678421.2017.1281961
M. Tesauro, M. Consonni, T. Filippini, L. Mazzini, F. Pisano, A. Chiò, Aniello Esposito, M. Vinceti
Abstract Objective and methods: Based on nationwide death certificates, a cluster of amyotrophic lateral sclerosis (ALS) has been reported in the area of Briga (Novara province, northern Italy), known for its severe environmental contamination. We further investigated this finding, by following up with the collection of recent incidence ALS data in 2002–2012 of Novara province, also to assess the possible long-term effects of environmental pollution in that area. Results: In the whole Novara province we identified 106 ALS cases, of which 35 were from the Briga area. Incidence rates of Novara province were 3.98, 5.14 and 2.97 for the total population, males and females, respectively, compared with the Briga area where they were 4.65, 4.27 and 4.98, respectively. The ratio of observed-to-expected ALS cases in the Briga area, using incidence of the rest of Novara province as a reference, was 1.17 (95% CI 0.81–1.62), with a value of 0.83 (95% CI 0.47–1.37) in males and 1.68 (95% CI 1.03–2.60) in females. Conclusions: Overall, our study did not confirm previous findings of an excess ALS incidence in an area characterised by severe environmental heavy metal pollution, and it suggests the need to interpret with caution clusters identified through mortality data.
目的与方法:根据全国死亡证明，在意大利北部诺瓦拉省布里加地区报告了一起肌萎缩性侧索硬化症(ALS)聚集性病例，该地区以环境污染严重而闻名。我们进一步调查了这一发现，通过收集诺瓦拉省2002-2012年最近ALS发病率的数据，也评估了该地区环境污染可能产生的长期影响。结果:在整个Novara省，我们发现106例ALS病例，其中35例来自Briga地区。诺瓦拉省总人口、男性和女性发病率分别为3.98、5.14和2.97，布里加地区发病率分别为4.65、4.27和4.98。以诺瓦拉省其他地区的发病率为参考，布里加地区的ALS观察病例与预期病例之比为1.17 (95% CI 0.81-1.62)，其中男性为0.83 (95% CI 0.47-1.37)，女性为1.68 (95% CI 1.03-2.60)。结论:总的来说，我们的研究并没有证实之前的研究结果，即在环境重金属污染严重的地区ALS发病率过高，这表明需要谨慎解释通过死亡率数据确定的聚类。
{"title":"Incidence of amyotrophic lateral sclerosis in the province of Novara, Italy, and possible role of environmental pollution","authors":"M. Tesauro, M. Consonni, T. Filippini, L. Mazzini, F. Pisano, A. Chiò, Aniello Esposito, M. Vinceti","doi":"10.1080/21678421.2017.1281961","DOIUrl":"https://doi.org/10.1080/21678421.2017.1281961","url":null,"abstract":"Abstract Objective and methods: Based on nationwide death certificates, a cluster of amyotrophic lateral sclerosis (ALS) has been reported in the area of Briga (Novara province, northern Italy), known for its severe environmental contamination. We further investigated this finding, by following up with the collection of recent incidence ALS data in 2002–2012 of Novara province, also to assess the possible long-term effects of environmental pollution in that area. Results: In the whole Novara province we identified 106 ALS cases, of which 35 were from the Briga area. Incidence rates of Novara province were 3.98, 5.14 and 2.97 for the total population, males and females, respectively, compared with the Briga area where they were 4.65, 4.27 and 4.98, respectively. The ratio of observed-to-expected ALS cases in the Briga area, using incidence of the rest of Novara province as a reference, was 1.17 (95% CI 0.81–1.62), with a value of 0.83 (95% CI 0.47–1.37) in males and 1.68 (95% CI 1.03–2.60) in females. Conclusions: Overall, our study did not confirm previous findings of an excess ALS incidence in an area characterised by severe environmental heavy metal pollution, and it suggests the need to interpret with caution clusters identified through mortality data.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2017.1281961","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45025152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-31DOI: 10.1080/21678421.2017.1280509
D. Czell, P. Sapp, C. Neuwirth, Markus Weber, P. Andersen, Robert H. Brown
Abstract A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.
{"title":"Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden","authors":"D. Czell, P. Sapp, C. Neuwirth, Markus Weber, P. Andersen, Robert H. Brown","doi":"10.1080/21678421.2017.1280509","DOIUrl":"https://doi.org/10.1080/21678421.2017.1280509","url":null,"abstract":"Abstract A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2017.1280509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44815547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-13DOI: 10.1080/21678421.2016.1272615
T. Burke, K. Lonergan, Marta Pinto-Grau, M. Elamin, P. Bede, Caoifa Madden, O. Hardiman, N. Pender
Abstract Objective: This study aimed to illustrate the variation of non-executive cognitive processes, i.e. visual memory, considering executive dysfunction in amyotrophic lateral sclerosis (ALS). Methods: Patients with ALS (n = 203), and matched healthy controls (n = 117) completed a battery of neuropsychological tests. Sub-stratification was based on whether cognitive assessment detected no cognitive abnormalities (NCA: n = 117), multiple executive cognitive deficits (ALS-Exec; n = 56), or a comorbid frontotemporal dementia process (ALS-FTD; n = 30). The Rey-Osterrieth Complex Figure Test (ROCFT) was the main dependent variable for visual memory in this study. Results: Patients and controls significantly differed on the Copy trial (p < 0.0001: ω2 = 0.317) immediate recall (p < 0.0001: ω2 = 0.272) and delayed recall (p < 0.0001: ω2 = 0.308) of the ROCFT. Sub-stratification based on executive dysfunction revealed an association with greater executive dysfunction and lower ROCFT performance. Regression analysis predicted that premorbid IQ, executive function, and demographics predict performance on the ROCFT delayed recall trial (R2 = 0.833). Conclusions: These findings illustrate that patients without executive dysfunction do not show visual memory impairments within this cohort; that patients with executive dysfunction have poorer performance on visual memory tasks; and that the severity of executive dysfunction, as per cognitive categorisation, is related to increased visual memory impairment as tested with the ROCFT.
{"title":"Visual encoding, consolidation, and retrieval in amyotrophic lateral sclerosis: executive function as a mediator, and predictor of performance","authors":"T. Burke, K. Lonergan, Marta Pinto-Grau, M. Elamin, P. Bede, Caoifa Madden, O. Hardiman, N. Pender","doi":"10.1080/21678421.2016.1272615","DOIUrl":"https://doi.org/10.1080/21678421.2016.1272615","url":null,"abstract":"Abstract Objective: This study aimed to illustrate the variation of non-executive cognitive processes, i.e. visual memory, considering executive dysfunction in amyotrophic lateral sclerosis (ALS). Methods: Patients with ALS (n = 203), and matched healthy controls (n = 117) completed a battery of neuropsychological tests. Sub-stratification was based on whether cognitive assessment detected no cognitive abnormalities (NCA: n = 117), multiple executive cognitive deficits (ALS-Exec; n = 56), or a comorbid frontotemporal dementia process (ALS-FTD; n = 30). The Rey-Osterrieth Complex Figure Test (ROCFT) was the main dependent variable for visual memory in this study. Results: Patients and controls significantly differed on the Copy trial (p < 0.0001: ω2 = 0.317) immediate recall (p < 0.0001: ω2 = 0.272) and delayed recall (p < 0.0001: ω2 = 0.308) of the ROCFT. Sub-stratification based on executive dysfunction revealed an association with greater executive dysfunction and lower ROCFT performance. Regression analysis predicted that premorbid IQ, executive function, and demographics predict performance on the ROCFT delayed recall trial (R2 = 0.833). Conclusions: These findings illustrate that patients without executive dysfunction do not show visual memory impairments within this cohort; that patients with executive dysfunction have poorer performance on visual memory tasks; and that the severity of executive dysfunction, as per cognitive categorisation, is related to increased visual memory impairment as tested with the ROCFT.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2017-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1272615","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48055240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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