1,548 research outputs found
Lancet Neurol
The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.R01 TS000327/TS/ATSDR CDC HHSUnited States/K23 ES027221/ES/NIEHS NIH HHSUnited States/MR/L501529/1/MRC_/Medical Research CouncilUnited Kingdom/R01 ES030049/ES/NIEHS NIH HHSUnited States/R01 NS120926/NS/NINDS NIH HHSUnited States/R01 NS127188/NS/NINDS NIH HHSUnited States/MR/R024804/1/MRC_/Medical Research CouncilUnited Kingdom/R01 TS000289/TS/ATSDR CDC HHSUnited States
Predicting functional impairment trajectories in amyotrophic lateral sclerosis: a probabilistic, multifactorial model of disease progression.
To employ Artificial Intelligence to model, predict and simulate the amyotrophic lateral sclerosis (ALS) progression over time in terms of variable interactions, functional impairments, and survival. We employed demographic and clinical variables, including functional scores and the utilisation of support interventions, of 3940 ALS patients from four Italian and two Israeli registers to develop a new approach based on Dynamic Bayesian Networks (DBNs) that models the ALS evolution over time, in two distinct scenarios of variable availability. The method allows to simulate patients' disease trajectories and predict the probability of functional impairment and survival at different time points. DBNs explicitly represent the relationships between the variables and the pathways along which they influence the disease progression. Several notable inter-dependencies were identified and validated by comparison with literature. Moreover, the implemented tool allows the assessment of the effect of different markers on the disease course, reproducing the probabilistically expected clinical progressions. The tool shows high concordance in terms of predicted and real prognosis, assessed as time to functional impairments and survival (integral of the AU-ROC in the first 36 months between 0.80-0.93 and 0.84-0.89 for the two scenarios, respectively). Provided only with measurements commonly collected during the first visit, our models can predict time to the loss of independence in walking, breathing, swallowing, communicating, and survival and it can be used to generate in silico patient cohorts with specific characteristics. Our tool provides a comprehensive framework to support physicians in treatment planning and clinical decision-making. [Abstract copyright: © 2022. The Author(s).
Biological and technical advances in therapies for amyotrophic lateral sclerosis disease
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.A Esclerose Lateral Amiotrófica (ELA) é uma doença neurodegenerativa fatal, caracterizada pela perda de neurónios motores e atrofia muscular progressiva. A ELA pode ser classificada em familiar (10% dos casos) se derivar de um padrão de hereditariedade autossómica dominante, ou esporádica (10%) se não estiver associada a um historial familiar. A ELA pode também ser classificada como bulbar ou medular, dependendo do local de origem. O seu prognóstico é a morte do paciente por falência respiratória, 2 a 5 anos após o inÃcio dos sintomas.
A ELA pode ter diversas manifestações motoras tais como fraqueza muscular progressiva, degeneração, fasciculações e contrações, mas também manifestações extra-motoras podendo ir ao encontro do diagnóstico de demência fronto-temporal (DFT).
As causas da ELA não são claras, porém existem diversos mecanismos patológicos associados. Uma das principais causas genéticas é a mutação no gene SOD1, causando patogenicidade através da perda de funções na proteÃna codificante assim como a sua agregação em neurónios motores e células da glia, despoletando outros mecanismos tais como neuro-inflamação, que contribuem para a progressão da doença. A causa genética mais comum é a expansão repetida hexanucleotÃdica no gene C9orf72, responsável pela maioria dos casos de ELA/DFT e cerca de 40% dos casos familiares de ELA.
Todas essas complicações tornam a vida dos pacientes bastante complicada. Infelizmente, não existem muitos medicamentos modificadores da doença aprovados para o tratamento da ELA, tornando o tratamento muito focado na gestão dos sintomas e na ajuda da melhoria da qualidade de vida dos pacientes. Os únicos medicamentos aprovados no mercado são o riluzol e o edaravone.
O objetivo principal desta monografia é fornecer uma visão geral e atualizada da doença em 2020 e a revisão das terapêuticas mais promissores a ser desenvolvidas de momento e respetivos ensaios clÃnicos de fase I, II e II.Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons and progressive muscular atrophy. ALS can be characterized as familial ALS (10% of the cases) if it has autosomal dominant inheritance patter or sporadic ALS (90% of the cases) if there is no family history. It can also be characterized in bulbar ALS or spinal ALS depending on the onset point. Its prognostic often is death by respiratory failure, 2 to 5 years after disease onset.
ALS can have very different motor manifestations such as progressive muscle weakness, wasting, fasciculations and cramps, but also non motor manifestations, a lot of the times meeting the diagnosis of fronto-temporal dementia.
What causes ALS is not clear, but there are a lot of genetic and pathological mechanisms studied that are associated with it. One of the main genetic cause is a mutation in SOD1 gene, causing pathogenesis by loss-of-functions of the codifying protein and cytoplasmic aggregations in neurons and glial cells, triggering other mechanisms such as neuroinflammation that contribute to disease progression. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for most cases of ALS/FTD and about 40% of familial cases of ALS.
All those complications make a very difficult life for patients to take. Unfortunately, there are not so many disease-modifying drugs approved for the treatment of ALS, making treatment very focused in symptom management and in helping patients to have a better life quality. The only two drugs approved are riluzole and edaravone.
The main objective of this dissertation is to give an updated overview of the disease in 2020, and review some of the most promising studies being made concerning new therapy ideas and phase I, II and III clinical trials
T cell responses in amyotrophic lateral sclerosis : friends or foes?
Amyotrophic lateral sclerosis (ALS) is an idiopathic fatal neurodegenerative disease that
is characterized by the loss of upper and lower motor neurons. Inflammation is widely
recognized as a hallmark of this disease; however, the intricate relationship between
immune biomarkers and the pathogenesis of ALS is not fully understood yet. In this
multidisciplinary thesis, by integrating multiple cohorts and employing diverse research
methodologies, we delved deeper into the complex interplay of immune system
dynamics and its impact on the risk, progression, and outcomes of this debilitating
neurodegenerative disease.
Study I conducted within a longitudinal population-based cohort explored the
associations between blood and urine biomarkers and the future risk of ALS and
Parkinson’s disease (PD). Although increasing concentrations of leukocytes, haptoglobin,
and uric acid were associated with a lower risk of PD, no statistically significant
associations were noted between the studied biomarkers and the risk of future ALS
diagnosis. By analyzing repeated biomarker measurements, the study described the
temporal changes of these biomarkers during the two decades preceding the diagnosis
of these diseases, shedding light on the dynamic nature of the immune biomarkers during
disease development. While levels of leukocytes and uric acid were consistently lower in
PD cases compared to controls, we did not observe any consistent differences in the
studied biomarkers between ALS cases and their matched controls.
Study II investigated the contribution of T cell responses to disease pathology by using
flow cytometric analysis of blood and cerebrospinal fluid (CSF) samples from a cohort of
newly diagnosed ALS patients. Our findings suggested that T cell phenotypes, at the time
of diagnosis, have the potential to serve as predictors of disease outcomes. A high
frequency of CD4+FOXP3- effector T cells in both blood and CSF was associated with poor
survival, while a high frequency of activated regulatory T cells and a high ratio of activated
to resting regulatory T cells in blood were associated with better survival. Additionally,
phenotypic profiling of T cells proved effective in predicting disease progression rate.
Furthermore, single cell transcriptomic analysis of CSF samples revealed presence of
clonally expanded CD4+ and CD8+ T cells with distinct gene expression patterns, further
supporting the involvement of T cell responses in ALS progression and suggesting the
modulation of adaptive immunity as a potential therapeutic avenue.
Study III expanded the exploration of T cell responses in ALS by studying the temporal
changes of these cells following ALS diagnosis. By phenotyping T cell subtypes
longitudinally in the blood and CSF of ALS patients, we highlighted the predictive value of
these cells in assessing disease progression. Moreover, higher levels of certain cell types,
including CD3+ and CD8+ T cells, were associated with increased mortality in the months
following measurement. These findings underscore the significance of T cells in
monitoring the disease course and mortality in ALS.
Additionally, this thesis book emphasizes the importance of methodological approaches
such as data collection and analysis. Study IV highlighted the significance of analytical
choices such as cohort size, follow-up time, sampling time, and choice of confounders in
the context of survival analysis in ALS and their contributions to the interpretation of
results.
Building upon findings in Studies II and III, where the T cell subsets did not render similar
associations with the disease outcome between blood and CSF, we aimed to contrast the
T cell profiles between the two biospecimens. In Study V, leveraging data from a
longitudinal cohort of ALS patients, we observed a weak association between the
frequency of T cell subsets in blood and CSF, suggesting that the phenotypic
characteristics of T cells in blood and their subsequent associations with ALS pathological
features would not necessarily reflect those of the central nervous system.
In conclusion, the findings of this thesis work offer valuable insights into potential
prognostic assessments and potential therapeutic interventions in ALS, as well as help
advance our understanding of this devastating disease and pave the way not only for
future research but also for improved patient care and management
A review of cases of motor neurone disease seen at Groote Schuur Hospital from 2005 to 2010
Includes bibliographical references.Motor neurone disease (MND) is a rare progressive neurodegenerative disorder in which selective degeneration of the motor neurones of the brain and spinal cord occurs. Progressive weakness of limb, bulbar and respiratory muscles eventually results in death. Most descriptive and epidemiological studies of MND have been performed in the industrialized countries of Europe and North America. We know very little about the incidence or prevalence of MND in Africa in general and South Africa in particular. However, anecdotal evidence based on observations by clinicians in the neurology and geriatric medical clinics at Groote Schuur Hospital suggest that the condition is not uncommonly seen, even in younger patients. Furthermore, many cases appear to originate from the West Coast area of the Western Cape. The proposed study aimed at describing the demographic and clinical characteristics of MND seen at Groote Schuur Hospital between 2005 and 2010. I hypothesized that disease duration, measured from age of onset of first symptoms to death, would be shorter in patients with bulbar-onset disease, in younger-onset disease, and in patients with higher CSF protein and blood creatine kinase levels at baseline. Furthermore, age of onset of the disease would be younger in familial compared with sporadic MND. I also hypothesized that smoking and certain occupational exposures might be risk factors for MND, that there would be a male preponderance of the disease, and that a disproportionate number of cases would come from the West Coast region. This was a retrospective study. I reviewed the clinical notes of cases of motor neurone disease and collected data relevant to the aims and hypotheses described above. I applied the El Escorial diagnostic criteria for MND to check the validity of the diagnoses. Mortality data were obtained through the Burden of Diseases Research Unit at the South African Medical Research Council. Forty eight patients were identified who met El Escorial criteria for the diagnosis of probable or definite MND. The median age of onset of the disease was 54 (IQR 47-63) and the mean duration of the disease from earliest symptoms to death was 2 years (IQR 1-3). These did not differ significantly between bulbar and limb-onset disease sub-types. There was a male preponderance of the disease (60%) and the majority of patients (60%) were smokers. African patients tended to have a younger age of onset. Occupations involving potential exposure to chemicals were disproportionately represented in the MND patients compared with the general population of the Western Cape. People from the West Coast region were not disproportionately represented in the patient population. Baseline CSF protein and serum creatine kinase levels were not associated with disease duration. The characteristics of MND cases seen at Groote Schuur Hospital between 2005 and 2010 are similar to those described in the world literature. Smoking and chemical exposure may be risk factors for the disease. There was no evidence of clustering of cases. This study will serve as the basis for future larger prospective studies on MND prevalence and aetiology in South Africa
Controversies and priorities in amyotrophic lateral sclerosis
Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events
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