Pub Date : 2019-10-31DOI: 10.1080/21678421.2019.1646991
Shu Yang, Sharlynn Wu, J. Fifita, E. McCann, S. C. M. Fat, J. Galper, S. Freckleton, Kathrine Y. Zhang, I. Blair
Background: Ongoing disease gene discoveries continue to drive our understanding of the molecular and cellular mechanisms underlying ALS. Causative genes from 60% of ALS families have been identified using modern genetic techniques, but the causal gene defect is yet to be identified in the remaining 40% of families. These remaining families often do not follow true Mendelian inheritance patterns and are challenging to solve using traditional genetic analysis alone. In vitro and in vivo studies have become critical in assessing and validating these ALS candidate genes.Objectives: In this study, we aim to develop and validate the utility of an in vitro functional pipeline for the discovery and validation of novel ALS candidate genes.Methods: A panel of cell based-assays were applied to candidate genes to examine the presence/absence of known ALS pathologies in cell lines as well as human autopsy tissues. These include immunofluorescence, flow cytometry and western blotting to study toxicity, neuronal inclusion formation, interaction with TDP-43, aberrant protein degradation and accumulation in detergent-insoluble cellular fractions. Immunohistochemistry and immunofluorescence were also used to examine if candidates were present in neuronal inclusions from ALS patient spinal cord tissues.Results: The in vitro pipeline was applied to five candidate genes from an ALS family that is negative for known ALS gene mutations. Two candidates were prioritized as top candidates based on their capacity to induce known ALS cellular pathologies. In transfected cells, the variants in these two genes caused a significantly higher toxicity than wild type, formed detergent insoluble inclusions and was able to co-aggregate with TDP-43 in neuronal cells. The variants have also led to protein degradation defects. One of the candidates also co-localised with TDP-43-positive neuronal inclusions in sporadic ALS patient post-mortem tissues, a signature pathology of ALS.Discussion and conclusions: We have demonstrated the utility of a functional prioritization pipeline and successfully prioritized two novel candidate ALS genes. These genes, and its associated pathways, will be further investigated through the development of animal models to establish if there is support for its role in ALS. New ALS genes offer fresh diagnostic and therapeutic targets and tools for the generation of novel animal models to better understand disease biology and offer preclinical testing of candidate treatments for ALS in the future.
{"title":"Theme 3 In vitro experimental models","authors":"Shu Yang, Sharlynn Wu, J. Fifita, E. McCann, S. C. M. Fat, J. Galper, S. Freckleton, Kathrine Y. Zhang, I. Blair","doi":"10.1080/21678421.2019.1646991","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646991","url":null,"abstract":"Background: Ongoing disease gene discoveries continue to drive our understanding of the molecular and cellular mechanisms underlying ALS. Causative genes from 60% of ALS families have been identified using modern genetic techniques, but the causal gene defect is yet to be identified in the remaining 40% of families. These remaining families often do not follow true Mendelian inheritance patterns and are challenging to solve using traditional genetic analysis alone. In vitro and in vivo studies have become critical in assessing and validating these ALS candidate genes.Objectives: In this study, we aim to develop and validate the utility of an in vitro functional pipeline for the discovery and validation of novel ALS candidate genes.Methods: A panel of cell based-assays were applied to candidate genes to examine the presence/absence of known ALS pathologies in cell lines as well as human autopsy tissues. These include immunofluorescence, flow cytometry and western blotting to study toxicity, neuronal inclusion formation, interaction with TDP-43, aberrant protein degradation and accumulation in detergent-insoluble cellular fractions. Immunohistochemistry and immunofluorescence were also used to examine if candidates were present in neuronal inclusions from ALS patient spinal cord tissues.Results: The in vitro pipeline was applied to five candidate genes from an ALS family that is negative for known ALS gene mutations. Two candidates were prioritized as top candidates based on their capacity to induce known ALS cellular pathologies. In transfected cells, the variants in these two genes caused a significantly higher toxicity than wild type, formed detergent insoluble inclusions and was able to co-aggregate with TDP-43 in neuronal cells. The variants have also led to protein degradation defects. One of the candidates also co-localised with TDP-43-positive neuronal inclusions in sporadic ALS patient post-mortem tissues, a signature pathology of ALS.Discussion and conclusions: We have demonstrated the utility of a functional prioritization pipeline and successfully prioritized two novel candidate ALS genes. These genes, and its associated pathways, will be further investigated through the development of animal models to establish if there is support for its role in ALS. New ALS genes offer fresh diagnostic and therapeutic targets and tools for the generation of novel animal models to better understand disease biology and offer preclinical testing of candidate treatments for ALS in the future.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646991","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46510031","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 : 2019-10-31DOI: 10.1080/21678421.2019.1647000
R. Ahmed, E. Devenney, C. Strikwerda-Brown, J. Hodges, O. Piguet, M. Kiernan
Background: Within the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum there is considerable heterogeneity in clinical presentation and survival.Objectives: The current study aimed to examine how initial symptoms (motor compared to cognitive) may affect survival, with specific focus on structural cognitive and behavioural differences between ALS-FTD and bvFTD cohorts.Methods: Cognitive and behavioural profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD patients). The initial presentation of ALS-FTD was categorized into either motor or cognitive, based on symptoms combined with carer reports. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale.Results: In the ALS-FTD group, 69% were categorized as having an initial cognitive presentation and 31% a motor presentation. Those patients with motor presentation of ALS-FTD experienced a significantly shorter survival of 33 months, compared to 63 months (p<0.007) in those with a cognitive presentation of ALS-FTD. On cognitive testing there were no differences between motor versus cognitive onset ALS-FTD. When compared to bvFTD, ALS-FTD, particularly the cognitive presentation, was characterized by reduced language function (p<0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both cognitive and motor presentation ALS-FTD had poorer emotion processing (p = 0.01) compared to bvFTD. On structural imaging analyses both motor and cognitive onset ALS-FTD patients had greater motor cortex and dorsal lateral prefrontal cortex atrophy compared to bvFTD patients. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival.Discussion and conclusions: In ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar overall cognitive impairment, suggesting that disease progression in ALS-FTD may be critically linked to physiological and motor changes. Survival is also associated with motor cortex atrophy which is increased in ALS-FTD.These results provide further suggestions in relation to the categorization of clinical trial patients into fast and slow progressors.
{"title":"Theme 11 Cognitive and psychological assessment and support","authors":"R. Ahmed, E. Devenney, C. Strikwerda-Brown, J. Hodges, O. Piguet, M. Kiernan","doi":"10.1080/21678421.2019.1647000","DOIUrl":"https://doi.org/10.1080/21678421.2019.1647000","url":null,"abstract":"Background: Within the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum there is considerable heterogeneity in clinical presentation and survival.Objectives: The current study aimed to examine how initial symptoms (motor compared to cognitive) may affect survival, with specific focus on structural cognitive and behavioural differences between ALS-FTD and bvFTD \u2028cohorts.Methods: Cognitive and behavioural profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD patients). The initial presentation of ALS-FTD was categorized into either motor or cognitive, based on symptoms combined with carer reports. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale.Results: In the ALS-FTD group, 69% were categorized as having an initial cognitive presentation and 31% a motor presentation. Those patients with motor presentation of ALS-FTD experienced a significantly shorter survival of 33 months, compared to 63 months (p<0.007) in those with a cognitive presentation of ALS-FTD. On cognitive testing there were no differences between motor versus cognitive onset ALS-FTD. When compared to bvFTD, ALS-FTD, particularly the cognitive presentation, was characterized by reduced language function (p<0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both cognitive and motor presentation ALS-FTD had poorer emotion processing (p = 0.01) compared to bvFTD. On structural imaging analyses both motor and cognitive onset ALS-FTD patients had greater motor cortex and dorsal lateral prefrontal cortex atrophy compared to bvFTD patients. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival.Discussion and conclusions: In ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar overall cognitive impairment, suggesting that disease progression in ALS-FTD may be critically linked to physiological and motor changes. Survival is also associated with motor cortex atrophy which is increased in ALS-FTD.These results provide further suggestions in relation to the categorization of clinical trial patients into fast and slow progressors.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76046691","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 : 2019-10-31DOI: 10.1080/21678421.2019.1646998
Background: MND is a progressive neurodegenerative disease characterised by death of upper and lower motor neurons, leading to progressive weakness of the bulbar, limb, thoracic and abdominal muscles. MND has a fairly stereotypical course, with death from respiratory failure occurring 2-4 years after symptom onset in most cases (1). Making the diagnosis of MND can be straightforward when key clinical criteria are met; however, at first presentation, rarely do patients meet these criteria, neurological changes may be subtle and disease progression slow. Thus, diagnosis poses a significant challenge, particularly in general practice, where patients are most likely to first present. Not surprisingly, there is usually a delay of 10-18 months between symptom onset and MND diagnosis (2). Importantly, early assessment by a neurologist is associated with a shorter time to MND diagnosis (3), which has significant implications for access to healthcare, including Riluzole and multidisciplinary clinics, which improve survival (4). Although delay in diagnosis is well documented, there have been no studies that have sought to identify factors associated with time to diagnosis, thereby enabling targeted implementation of a public health intervention.Objectives: To characterise the clinical factors that influence time to diagnosis of MND.Methods: 112 patients with MND attending the Southern Adelaide MND Clinic enrolled between January 2016 - 2018 were retrospectively recruited in to a cohort study. Information pertaining to the patient's demographics and their journey to diagnosis collected by a specialist physician and stored in the Australian MND Registry during clinic review were analysed to identify factors associated with time to diagnosis.Results: Mean time to diagnosis was 13 ± 1 months (range 1 - 38 months) from symptom onset. 41% of patients were classified as having fast disease progression; compared to those with slow disease progression, these patients were diagnosed earlier (8 ± 1 months vs 16 ± 2 months) (p < 0.0001, t = 34.6, df =220), were less likely to undergo multiple specialist opinions prior to referral to a neurologist (53% vs 73%) (p < 0.05, Chi-squared = 9.5, df =1), and were more disabled at time of diagnosis (mean ALSFRS-R 33 ± 5 vs ALSFRS-R 41 ± 5) (p < 0.0001, t = 12.4, df =220).Discussion and conclusions: Fast disease progression identifies a dichotomy of MND patients diagnosed earlier, although more disabled at diagnosis, likely mediated by a more efficient referral process. A greater awareness of MND is required to shorten time to diagnosis.
{"title":"Theme 10 Disease stratification and phenotyping of patients","authors":"","doi":"10.1080/21678421.2019.1646998","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646998","url":null,"abstract":"Background: MND is a progressive neurodegenerative disease characterised by death of upper and lower motor neurons, leading to progressive weakness of the bulbar, limb, thoracic and abdominal muscles. MND has a fairly stereotypical course, with death from respiratory failure occurring 2-4 years after symptom onset in most cases (1). Making the diagnosis of MND can be straightforward when key clinical criteria are met; however, at first presentation, rarely do patients meet these criteria, neurological changes may be subtle and disease progression slow. Thus, diagnosis poses a significant challenge, particularly in general practice, where patients are most likely to first present. Not surprisingly, there is usually a delay of 10-18 months between symptom onset and MND diagnosis (2). Importantly, early assessment by a neurologist is associated with a shorter time to MND diagnosis (3), which has significant implications for access to healthcare, including Riluzole and multidisciplinary clinics, which improve survival (4). Although delay in diagnosis is well documented, there have been no studies that have sought to identify factors associated with time to diagnosis, thereby enabling targeted implementation of a public health intervention.Objectives: To characterise the clinical factors that influence time to diagnosis of MND.Methods: 112 patients with MND attending the Southern Adelaide MND Clinic enrolled between January 2016 - 2018 were retrospectively recruited in to a cohort study. Information pertaining to the patient's demographics and their journey to diagnosis collected by a specialist physician and stored in the Australian MND Registry during clinic review were analysed to identify factors associated with time to diagnosis.Results: Mean time to diagnosis was 13 ± 1 months (range 1 - 38 months) from symptom onset. 41% of patients were classified as having fast disease progression; compared to those with slow disease progression, these patients were diagnosed earlier (8 ± 1 months vs 16 ± 2 months) (p < 0.0001, t = 34.6, df =220), were less likely to undergo multiple specialist opinions prior to referral to a neurologist (53% vs 73%) (p < 0.05, Chi-squared = 9.5, df =1), and were more disabled at time of diagnosis (mean ALSFRS-R 33 ± 5 vs ALSFRS-R 41 ± 5) (p < 0.0001, t = 12.4, df =220).Discussion and conclusions: Fast disease progression identifies a dichotomy of MND patients diagnosed earlier, although more disabled at diagnosis, likely mediated by a more efficient referral process. A greater awareness of MND is required to shorten time to diagnosis.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86586415","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 : 2019-10-31DOI: 10.1080/21678421.2019.1646996
Katarina Vogelnik, R. P. Alfonso, B. Koritnik, Polona Klavžar, L. Leonardis, L. D. Grošelj, J. Zidar, M. Kojović
Background: We have commonly observed involuntary jerks and tremor in patients with motor neuron disease (MND), even though these features are not considered typical for the disease.Objectives: We conducted prospective clinical and electrophysiological study to explore the prevalence, phenomenology and pathophysiology of involuntary movements in MND.Methods: Seventy-four consecutive patients were clinically examined and video-recorded. Based on regularity and distribution, movements observed at rest position were classified as minipolymyoclonus (MPMC) or rest thumb tremor (RTT) and movements present during action as action MPMC or action tremor. In 11 patients with tremor, accelerometry was recorded at (a) rest position, (b) with arms outstretched (postural condition) and (c) at postural condition with 500 g mass attached to the hand.Results: Involuntary movements were present in 54 patients (73%). Rest MPMC was present in 26 patients (35%), RTT in 22 patients (31%), action MPMC in 22 patients (30%) and action tremor in 20 patients (27%), with some overlap. Sixteen patients (22%) reported negative impact of involuntary movements on their ability to use hands. Regression model showed that lower distal muscle power and less prominent upper motor neuron involvement significantly increased the odds of MND patient having involuntary movements. Sex, age and disease duration did not significantly predict the occurrence of involuntary movements. At rest, tremor frequency ranged from 5.2 to 8.2 Hz, at postural position from 4.9 Hz to 7.6 Hz and during postural position with mass attached from 3.6 Hz to 7.6 Hz. On the group level, tremor peak frequency statistically significantly decreased from 6.1 Hz to 5 Hz without versus with loading.Discussion and conclusions: Involuntary movements are very common yet largely overlooked feature of MND that may also have negative impact on patient's functional abilities. Lower distal muscle power increases and the presence of upper motor neuron signs decreases the probability of involuntary movements. Together with finding of decrease in tremor frequency with mass loading, these results suggest that generation of involuntary movements is of peripheral origin.
{"title":"Theme 8 Clinical imaging and electrophysiology","authors":"Katarina Vogelnik, R. P. Alfonso, B. Koritnik, Polona Klavžar, L. Leonardis, L. D. Grošelj, J. Zidar, M. Kojović","doi":"10.1080/21678421.2019.1646996","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646996","url":null,"abstract":"Background: We have commonly observed involuntary jerks and tremor in patients with motor neuron disease (MND), even though these features are not considered typical for the disease.Objectives: We conducted prospective clinical and electrophysiological study to explore the prevalence, phenomenology and pathophysiology of involuntary movements in MND.Methods: Seventy-four consecutive patients were clinically examined and video-recorded. Based on regularity and distribution, movements observed at rest position were classified as minipolymyoclonus (MPMC) or rest thumb tremor (RTT) and movements present during action as action MPMC or action tremor. In 11 patients with tremor, accelerometry was recorded at (a) rest position, (b) with arms outstretched (postural condition) and (c) at postural condition with 500 g mass attached to the hand.Results: Involuntary movements were present in 54 patients (73%). Rest MPMC was present in 26 patients (35%), RTT in 22 patients (31%), action MPMC in 22 patients (30%) and action tremor in 20 patients (27%), with some overlap. Sixteen patients (22%) reported negative impact of involuntary movements on their ability to use hands. Regression model showed that lower distal muscle power and less prominent upper motor neuron involvement significantly increased the odds of MND patient having involuntary movements. Sex, age and disease duration did not significantly predict the occurrence of involuntary movements. At rest, tremor frequency ranged from 5.2 to 8.2 Hz, at postural position from 4.9 Hz to 7.6 Hz and during postural position with mass attached from 3.6 Hz to 7.6 Hz. On the group level, tremor peak frequency statistically significantly decreased from 6.1 Hz to 5 Hz without versus with loading.Discussion and conclusions: Involuntary movements are very common yet largely overlooked feature of MND that may also have negative impact on patient's functional abilities. Lower distal muscle power increases and the presence of upper motor neuron signs decreases the probability of involuntary movements. Together with finding of decrease in tremor frequency with mass loading, these results suggest that generation of involuntary movements is of peripheral origin.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78738437","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 : 2019-10-31DOI: 10.1080/21678421.2019.1646995
V. Lombardi, D. Carassiti, G. Giovannoni, Ching-Hua Lu, R. Adiutori, A. Malaspina
The rise of neurodegenerative disorders (NDD) in the ageing population is increasing demand on already stretched Health Services and is a major financial burden for society (1). The development of tools for early diagnosis is one of the responses to this problem (2). Cerebrospinal fluid (CSF) is the main repository of by-products of neuronal destruction (3); as serial lumbar punctures to procure CSF may be impractical in advanced patients (4), blood may represent the ideal source to track any meaningful disease signal of neurodegeneration.High-costs and low energy efficiency have pushed alternative means of samples collection and storage. Noviplex dried plasma spot (Np-DPS) and dried blood spot (DBS) on filter paper can be a remote, quick and inexpensive way of obtaining blood microsamples for the measurement of a large number of analytes in non-hospitalized, public health settings (5).We have used commercially-available and highly sensitive immunodetection assays (6) to test neurofilament light chain (Nf-L) expression in elute from DBS and from Np-DPS and compared these to standard Nf-L plasma measurement of healthy controls and patients with amyotrophic lateral sclerosis (ALS).We show that DBS and Np-DP cards can be used for remote blood collection and measurement of Nf-L. Nf-L measurement using elute from Noviplex DPS cards is equivalent to that obtained in plasma from the same blood samples, while levels of the same analyte in DBS elute are different, but provide discrimination between controls and ALS patients. Normalization using known loading protein concentration may also be needed for DBS analysis to adjust for the chromatographic effect of retained haemoglobin in the spot elute. Conversely, a simple elution step is required for Np-DPS, which reconstitutes a test fluid which is indistinguishable from plasma originated by conventional blood processing.
{"title":"Theme 7 Pre-clinical therapeutic strategies","authors":"V. Lombardi, D. Carassiti, G. Giovannoni, Ching-Hua Lu, R. Adiutori, A. Malaspina","doi":"10.1080/21678421.2019.1646995","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646995","url":null,"abstract":"The rise of neurodegenerative disorders (NDD) in the ageing population is increasing demand on already stretched Health Services and is a major financial burden for society (1). The development of tools for early diagnosis is one of the responses to this problem (2). Cerebrospinal fluid (CSF) is the main repository of by-products of neuronal destruction (3); as serial lumbar punctures to procure CSF may be impractical in advanced patients (4), blood may represent the ideal source to track any meaningful disease signal of neurodegeneration.High-costs and low energy efficiency have pushed alternative means of samples collection and storage. Noviplex dried plasma spot (Np-DPS) and dried blood spot (DBS) on filter paper can be a remote, quick and inexpensive way of obtaining blood microsamples for the measurement of a large number of analytes in non-hospitalized, public health settings (5).We have used commercially-available and highly sensitive immunodetection assays (6) to test neurofilament light chain (Nf-L) expression in elute from DBS and from Np-DPS and compared these to standard Nf-L plasma measurement of healthy controls and patients with amyotrophic lateral sclerosis (ALS).We show that DBS and Np-DP cards can be used for remote blood collection and measurement of Nf-L. Nf-L measurement using elute from Noviplex DPS cards is equivalent to that obtained in plasma from the same blood samples, while levels of the same analyte in DBS elute are different, but provide discrimination between controls and ALS patients. Normalization using known loading protein concentration may also be needed for DBS analysis to adjust for the chromatographic effect of retained haemoglobin in the spot elute. Conversely, a simple elution step is required for Np-DPS, which reconstitutes a test fluid which is indistinguishable from plasma originated by conventional blood processing.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646995","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45879783","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 : 2019-10-31DOI: 10.1080/21678421.2019.1646997
Tara Lincoln, C. Allen
Background: NEALS is a non-profit organization that aims to successfully promote both research and awareness of ALS, encouraging collaborations among clinicians, researchers, and industry through a commitment to open scientific communication. The efforts of NEALS members are recognized by disease foundations, research groups, and industry, generating critical support through awards and project funding.Objectives: Bringing together a group of distinguished scientists and researchers over the nearly quarter century since its inception, NEALS has developed novel research approaches and recruited a number of new investigators into the field of ALS research in an effort to accelerate ALS clinical trials through academic input and partnership.Methods: The NEALS Consortium adheres to an inclusive policy of adding clinical sites wherever there is interest and expertise, improving access to trials in regions where trial participation was not previously available. NEALS sites include 127 academic ALS trial centers in the United States, Canada, Mexico, Lebanon, Italy, Australia and Israel.Education and Participation of the PALS Community in Clinical ResearchAnnual Clinical Research Learning InstitutePALS & CALS as Research AmbassadorsAdvocacy efforts by Research AmbassadorsNEALS website & clinical trial database: http://www. neals.orgResults: The numerous trials run by NEALS-affiliated Principal Investigators and/or Centers is used as a broad benchmark of success for the Consortium. Additionally, the growth of participation in studies by people with ALS has been used as a similar outcome measure when assessing the success of the organization. The research done by NEALS members, paired with the membership's commitment to a coordinated effort, give the NEALS Consortium a unique role, one with top credibility in the community of people with ALS (PALS). The strong relationship between the Consortium's research members and PALS is substantiated by the increasing participation of PALS in the organization's research efforts. Since 1999, 125,286 PALS have participated in NEALS studies. In 2018 alone, 4,173 people with ALS participated in NEALS trials, up significantly from 1999's participation (n=101).Discussion and conclusions: It is more critical than ever for healthcare professionals to underscore the importance of clinical research into the causes and treatments of ALS and associated conditions. In this vision for the future, by involving more people in ALS research and ensuring that they and those around them are properly informed about the disease, public knowledge regarding rare disease research grows, allowing the research community to give back to the patient population through science breakthroughs and increased disease knowledge.
{"title":"Theme 9 Clinical trials and trial design","authors":"Tara Lincoln, C. Allen","doi":"10.1080/21678421.2019.1646997","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646997","url":null,"abstract":"Background: NEALS is a non-profit organization that aims to successfully promote both research and awareness of ALS, encouraging collaborations among clinicians, researchers, and industry through a commitment to open scientific communication. The efforts of NEALS members are recognized by disease foundations, research groups, and industry, generating critical support through awards and project funding.Objectives: Bringing together a group of distinguished scientists and researchers over the nearly quarter century since its inception, NEALS has developed novel research approaches and recruited a number of new investigators into the field of ALS research in an effort to accelerate ALS clinical trials through academic input and partnership.Methods: The NEALS Consortium adheres to an inclusive policy of adding clinical sites wherever there is interest and expertise, improving access to trials in regions where trial participation was not previously available. NEALS sites include 127 academic ALS trial centers in the United States, Canada, Mexico, Lebanon, Italy, Australia and Israel.Education and Participation of the PALS Community in Clinical ResearchAnnual Clinical Research Learning InstitutePALS & CALS as Research AmbassadorsAdvocacy efforts by Research AmbassadorsNEALS website & clinical trial database: http://www.\u2028neals.orgResults: The numerous trials run by NEALS-affiliated Principal Investigators and/or Centers is used as a broad benchmark of success for the Consortium. Additionally, the growth of participation in studies by people with ALS has been used as a similar outcome measure when assessing the success of the organization. The research done by NEALS members, paired with the membership's commitment to a coordinated effort, give the NEALS Consortium a unique role, one with top credibility in the community of people with ALS (PALS). The strong relationship between the Consortium's research members and PALS is substantiated by the increasing participation of PALS in the organization's research efforts. Since 1999, 125,286 PALS have participated in NEALS studies. In 2018 alone, 4,173 people with ALS participated in NEALS trials, up significantly from 1999's participation (n=101).Discussion and conclusions: It is more critical than ever for healthcare professionals to underscore the importance of clinical research into the causes and treatments of ALS and associated conditions. In this vision for the future, by involving more people in ALS research and ensuring that they and those around them are properly informed about the disease, public knowledge regarding rare disease research grows, allowing the research community to give back to the patient population through science breakthroughs and increased disease knowledge.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82814312","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 : 2019-10-15DOI: 10.1080/21678421.2019.1674874
Faith Hodgins, S. Mulhern, S. Abrahams
Abstract Objectives. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a brief multi-domain assessment designed for people with Amyotrophic Lateral Sclerosis (ALS). This study evaluated the clinical impact of using the ECAS on ALS patients, carers and healthcare professionals. A secondary aim was to evaluate the clinical impact of neuropsychological intervention. Methods. A survey of current screening practices in ALS services across the UK was undertaken. In addition comparative case studies, in seven ALS care contexts, was qualitatively explored through interviews with patients, carers and healthcare professionals. Results. 22/34 health care services responded to the survey. 95% screen patients for cognitive and behavioral changes and all used the ECAS. Thematic analysis indicated that the ECAS: raises awareness about cognitive and behavioral change between patients, carers and healthcare professionals; validates and/or reassures; identifies changes, aids understanding of the patients’ presentation and informs clinical decision-making. The latter includes suitability of interventions, adaptations by the multidisciplinary team, discussions about end-of-life care, referral on to other services, and identifying carers’ support needs. A number of indirect economic benefits were described. Clinical neuropsychological intervention was reported to help the multidisciplinary team manage the care particularly of complex cases, the effects on daily life, and stress of patients, carers and families. Conclusions. The ECAS has been widely implemented across ALS health care teams in the UK. Screening for cognitive/behavioral deficits and neuropsychological intervention has a positive impact on patients, carers and healthcare professionals and improves the quality of routine clinical care.
{"title":"The clinical impact of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and neuropsychological intervention in routine ALS care","authors":"Faith Hodgins, S. Mulhern, S. Abrahams","doi":"10.1080/21678421.2019.1674874","DOIUrl":"https://doi.org/10.1080/21678421.2019.1674874","url":null,"abstract":"Abstract Objectives. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a brief multi-domain assessment designed for people with Amyotrophic Lateral Sclerosis (ALS). This study evaluated the clinical impact of using the ECAS on ALS patients, carers and healthcare professionals. A secondary aim was to evaluate the clinical impact of neuropsychological intervention. Methods. A survey of current screening practices in ALS services across the UK was undertaken. In addition comparative case studies, in seven ALS care contexts, was qualitatively explored through interviews with patients, carers and healthcare professionals. Results. 22/34 health care services responded to the survey. 95% screen patients for cognitive and behavioral changes and all used the ECAS. Thematic analysis indicated that the ECAS: raises awareness about cognitive and behavioral change between patients, carers and healthcare professionals; validates and/or reassures; identifies changes, aids understanding of the patients’ presentation and informs clinical decision-making. The latter includes suitability of interventions, adaptations by the multidisciplinary team, discussions about end-of-life care, referral on to other services, and identifying carers’ support needs. A number of indirect economic benefits were described. Clinical neuropsychological intervention was reported to help the multidisciplinary team manage the care particularly of complex cases, the effects on daily life, and stress of patients, carers and families. Conclusions. The ECAS has been widely implemented across ALS health care teams in the UK. Screening for cognitive/behavioral deficits and neuropsychological intervention has a positive impact on patients, carers and healthcare professionals and improves the quality of routine clinical care.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1674874","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49167721","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 : 2019-10-11DOI: 10.1080/21678421.2019.1675710
R. V. van Eijk, L. H. van den Berg
The long list of futile clinical trials in amyotrophic lateral sclerosis (ALS) signifies the detrimental consequences of disease heterogeneity for effective drug development. The wide range of pathophysiological mechanisms underlying ALS results in a variety of clinical manifestations. As a consequence, trial populations consist of patients with varying degrees of disease severity, rates of decline and distributions of symptoms. This inflates the noise in efficacy endpoints and could disguise critical treatment clues. In order to improve the design of future clinical trials, defining a favorable patient population may benefit trial efficiency and increase the probability to detect effective compounds. In this issue of the Journal, Mora et al. illustrate the potential of excluding fast-progressing patients from clinical trials (1). The authors present a large randomized, placebo-controlled trial to investigate the efficacy and safety of Masitinib over a 48-week treatment period. Patients were classified into normal and fast progressing subgroups based on their baseline delta ALS functional rating scale (i.e. DFRS, defined as 48-ALSFRS-R score/ duration of symptoms (2)). Due to the lack of a molecular biomarker, the DFRS was used as indirect marker of disease aggressiveness. Interestingly, by excluding the fast progressors (defined as DFRS > 1.1) a treatment response appears in an otherwise futile trial population. Notwithstanding the inherited risks of subgroup analyses and the need for a confirmatory trial, Mora et al. report an intriguing observation that could be a valuable lesson for future clinical trials. The removal of patients with higher DFRS scores may have resulted in a less heterogeneous trial population, one that was more sensitive to detect a treatment response. Based on the PROACT database, we evaluated this hypothesis in Figure 1 where population heterogeneity is defined as the between-patient variability in ALSFRS progression rates after randomization. As can be seen, by including patients with higher DFRS scores, the between-patient variability in progression rates after randomization (red) increases and the trial population becomes more heterogeneous. Thus, by selecting patients with lower DFRS scores, one is able to make a more homogenous trial population, a phenomenon that may have benefited the Masitinib trial. However, Figure 1 also indicates that the removal of patients with higher DFRS scores additionally reduces the mean rate of decline after randomization (green). This is a critical observation and, in case one solely excludes patients with higher DFRS scores, the reduction in the mean rate of decline is larger than the reduction in the between-patient variability. As a result, the net effect of excluding patients with higher DFRS scores is a paradoxical worse signal-to-noise ratio, which could lower statistical power when implemented in future settings. This paradoxical result is partly driven by the relatively low pred
{"title":"In pursuit of the normal progressor: the holy grail for ALS clinical trial design?","authors":"R. V. van Eijk, L. H. van den Berg","doi":"10.1080/21678421.2019.1675710","DOIUrl":"https://doi.org/10.1080/21678421.2019.1675710","url":null,"abstract":"The long list of futile clinical trials in amyotrophic lateral sclerosis (ALS) signifies the detrimental consequences of disease heterogeneity for effective drug development. The wide range of pathophysiological mechanisms underlying ALS results in a variety of clinical manifestations. As a consequence, trial populations consist of patients with varying degrees of disease severity, rates of decline and distributions of symptoms. This inflates the noise in efficacy endpoints and could disguise critical treatment clues. In order to improve the design of future clinical trials, defining a favorable patient population may benefit trial efficiency and increase the probability to detect effective compounds. In this issue of the Journal, Mora et al. illustrate the potential of excluding fast-progressing patients from clinical trials (1). The authors present a large randomized, placebo-controlled trial to investigate the efficacy and safety of Masitinib over a 48-week treatment period. Patients were classified into normal and fast progressing subgroups based on their baseline delta ALS functional rating scale (i.e. DFRS, defined as 48-ALSFRS-R score/ duration of symptoms (2)). Due to the lack of a molecular biomarker, the DFRS was used as indirect marker of disease aggressiveness. Interestingly, by excluding the fast progressors (defined as DFRS > 1.1) a treatment response appears in an otherwise futile trial population. Notwithstanding the inherited risks of subgroup analyses and the need for a confirmatory trial, Mora et al. report an intriguing observation that could be a valuable lesson for future clinical trials. The removal of patients with higher DFRS scores may have resulted in a less heterogeneous trial population, one that was more sensitive to detect a treatment response. Based on the PROACT database, we evaluated this hypothesis in Figure 1 where population heterogeneity is defined as the between-patient variability in ALSFRS progression rates after randomization. As can be seen, by including patients with higher DFRS scores, the between-patient variability in progression rates after randomization (red) increases and the trial population becomes more heterogeneous. Thus, by selecting patients with lower DFRS scores, one is able to make a more homogenous trial population, a phenomenon that may have benefited the Masitinib trial. However, Figure 1 also indicates that the removal of patients with higher DFRS scores additionally reduces the mean rate of decline after randomization (green). This is a critical observation and, in case one solely excludes patients with higher DFRS scores, the reduction in the mean rate of decline is larger than the reduction in the between-patient variability. As a result, the net effect of excluding patients with higher DFRS scores is a paradoxical worse signal-to-noise ratio, which could lower statistical power when implemented in future settings. This paradoxical result is partly driven by the relatively low pred","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85548482","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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