Scientific Publications

This section encompasses all scientific publications generated by the project

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Deep learning methods to predict amyotrophic lateral sclerosis disease progression

Corrado Pancotti, Giovanni Birolo, Cesare Rollo, Tiziana Sanavia, Barbara Di Camillo, Umberto Manera, Adriano Chiò & Piero Fariselli

Amyotrophic lateral sclerosis (ALS) is a complex disease that weakens muscles by attacking nerve cells. Because ALS patients face shortened lifespans, understanding the disease’s progression quickly is crucial for improving treatments. Scientists are turning to computer models to forecast how ALS develops over time.
One major data source aiding this research is the PRO-ACT repository. In 2015, a competition challenged developers to create programs predicting ALS progression using this data.
Our study dives into this challenge, applying advanced Deep Learning techniques.
Our findings suggest that Deep Learning could offer a fresh approach to forecasting ALS progression, offering hope for more effective treatment strategies.

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Exposure to electromagnetic fields does not modify neither the age of onset nor the disease progression in ALS patients

Clinical perspective, Peer-reviewed, Journal

Vasta R, Callegaro S, Grassano M, Canosa A, Cabras S, Di Pede F, Matteoni E, De Mattei F, Casale F, Salamone P, Mazzini L, De Marchi F, Moglia C, Calvo A, Chiò A, Manera U

In this paper, we evaluate the effect of exposure to electromagnetic fields on ALS onset age and progression rate. We studied the association of patients’ residency with the distribution of power lines and repeater antennas. We did not find any significant relationship between electromagnetic fields and ALS phenotype or progression.

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Exploring the phenotype of Italian patients with ALS with intermediate ATXN2 polyQ repeats

Clinical perspective, Peer-reviewed, Journal

Chio A, Moglia C, Canosa A, Manera U, Grassano M, Vasta R, Palumbo F, Gallone S, Brunetti M, Barberis M, De Marchi F, Dalgard C, Chia R, Mora G, Iazzolino B, Peotta L, Traynor B, Corrado L, D’Alfonso S, Mazzini L, Calvo A

ATXN2 is a gene related to a neurodegenerative disease called Spinocerebellar Ataxia type 2, but it is also a recognised risk factor for ALS. In this study, we explored the role of the so-called intermediate repeated expansion (a specific type of mutations characterised by the wrong repetition of short sequences of DNA that produces altered amminoacidic sequences called polyQ) in the determination of ALS patients’ phenotype. We discovered that patients with these alterations showed an early age at onset and a higher progression rate. We confirmed that ATXN2 can be a potential target for new therapeutic approaches.

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Systematic evaluation of genetic mutations in ALS: a population-based study

Clinical perspective, Peer-reviewed, Journal

Grassano M, Calvo A, Moglia C, Sbaiz L, Brunetti M, Barberis M, Casale F, Manera U, Vasta R, Canosa A, D’Alfonso S, Corrado L, Mazzini L, Dalgard C, Karra R, Chia R, Traynor B, Chiò A

ALS is probably caused by an interplay between environmental and genetic factors. Several descriptions of patients carrying more than one pathogenic mutation are present in scientific literature, but few papers systematically evaluated the presence of mutations in ALS-related genes in population-based cohorts. In this study, we highlighted that the presence of more than one mutation is more common than expected. Patients with more than one mutation resulted to have more aggressive phenotypes, confirming that disease  features can be due to the malfunction of several neuronal pathways.

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Social cognition deficits in amyotrophic lateral sclerosis: A pilot cross-sectional population-based study

Clinical perspective, Peer-reviewed, Journal

Palumbo F, Iazzolino B, Peotta L, Canosa A, Manera U, Grassano M, Casale F, Pellegrino G, Rizzone MG, Vasta R, Moglia C, Chiò A, Calvo A

ALS is mainly a neurodegenerative disease involving motor system, but also some aspects of cognition can be impaired. Social cognition is one of the most important brain function in humans, being responsible for our social living and well-being. We prospectively studied a cohort of ALS patients belonging to Piedmont ALS registry using neuropsychological tests specifically designed for assess social cognition. ALS patients showed significant lower scores than healthy controls, confirming a social cognition deficit than needs to be taken into account in patients management.

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Respiratory onset in amyotrophic lateral sclerosis: clinical features and spreading pattern

Susana Pinto, Marta Gromicho, Miguel Oliveira Oliveira Santos, Michael Swash & Mamede De Carvalho

This study focused on persons with a rare type of ALS known as respiratory onset ALS. This type of ALS begins with breathing problems and affects the diaphragm muscle, which is essential for respiration.
The study discovered that most persons with respiratory onset ALS are elderly men who are underweight. They must begin utilizing non-invasive ventilation (NIV), which helps them breathe, earlier than patients with other types of ALS.
Despite NIV therapy, persons with respiratory onset ALS have a worse life expectancy than those with other types of ALS. The study also found that the pattern of how ALS spreads throughout the body does not affect how quickly people need NIV or how long they live.

 

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Thyroid dysfunction in Portuguese amyotrophic lateral sclerosis patients

Santos Silva C, Gromicho M, Oliveira Santos M, Pinto S, Swash M, de Carvalho

This study looked into whether thyroid dysfunction or an imbalance in the hormones produced by the thyroid gland, is linked to amyotrophic lateral sclerosis (ALS).
The researchers compared the prevalence of thyroid dysfunction in ALS patients to that of people with non-thyroid-related neuromuscular disorders. They discovered that ALS patients had a lower prevalence of thyroid dysfunction than the control group, indicating that thyroid dysfunction is not a major contributor to ALS development.
The researchers also reviewed previous studies on thyroid dysfunction and ALS and discovered that their findings were consistent with those of other studies.
Overall, this study suggests that thyroid dysfunction does not pose a significant risk for ALS.

 

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Mild dysphagia does not influence survival in ventilated amyotrophic lateral sclerosis patients

Miguel Oliveira Santos, Marta Gromicho, Susana Pinto, Michael Swash, Mamede de Carvalho

Swallowing problems, or dysphagia, are a common symptom of ALS. People with ALS who are on continuous non-invasive ventilation (NIV), a breathing treatment, frequently develop dysphagia.
Doctors often debate whether or not to insert a feeding tube called a gastrostomy in ALS patients who use NIV. A gastrostomy is a surgical procedure that delivers food directly to the stomach via a tube.
This study examined patients with ALS who were already using NIV and investigated whether mild dysphagia affected their survival. The researchers analyzed the data from these patients and discovered that mild dysphagia did not affect their survival.
This study is important because it provides information that helps doctors make decisions about gastrostomy in patients with ALS who use NIV. The findings suggest that mild dysphagia is not a major factor in survival for these patients.

 

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Learning prognostic models using a mixture of biclustering and triclustering: Predicting the need for non-invasive ventilation in Amyotrophic Lateral Sclerosis

Diogo F. Soares, Rui Henriques, Marta Gromicho, Mamede de Carvalho, Sara C. Madeira

This paper wants to improve the best features in methods used for predicting outcomes and deciding when patients with Amyotrophic Lateral Sclerosis (ALS) need non-invasive breathing assistance. It achieves this by studying clear patterns of how the disease progresses. The discoveries made can also be useful for understanding other aspects of ALS and similar diseases.

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Triclustering-based classification of longitudinal data for prognostic prediction: targeting relevant clinical endpoints in amyotrophic lateral sclerosis

Clinical perspective, Open Access, Journal

Diogo F. Soares, Rui Henriques, Marta Gromicho, Mamede de Carvalho, Sara C. Madeira

This research introduces a new type of understandable models for predicting how diseases progress over time, focusing on a specific group of patients with certain characteristics. We developed a new method called TCtriCluster, which looks for meaningful patterns in data collected over time from these patients, helping us understand the progression of the disease better. By using these patterns, we improved the accuracy of predicting important events in ALS, such as when patients might need breathing assistance or other types of support. This method performed better than existing ones, with high accuracy in predicting when certain interventions might be needed. This approach was tested on a large group of ALS patients in Portugal, providing valuable insights for healthcare professionals in managing the disease and its various stages.

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Artificial intelligence and statistical methods for stratification and prediction of progression in amyotrophic lateral sclerosis: A systematic review

Erica Tavazzi, Enrico Longato, Martina Vettoretti, Helena Aidos, Isotta Trescato, Chiara Roversi, Andreia S Martins, Eduardo N Castanho, Ruben Branco, Diogo F Soares, Alessandro Guazzo, Giovanni Birolo, Daniele Pala, Pietro Bosoni, Adriano Chiò, Umberto Manera, Mamede de Carvalho, Bruno Miranda, Marta Gromicho, Inês Alves, Riccardo Bellazzi, Arianna Dagliati, Piero Fariselli, Sara C Madeira, Barbara Di Camillo

This systematic review examines artificial intelligence’s methodological landscape in ALS, focusing on patient stratification and disease progression prediction.
Out of 1604 reports, we identified 15 studies on patient stratification, 28 on ALS progression prediction, and 6 on both. We highlighted a general agreement in terms of input variable selection for both stratification and prediction of ALS progression, and in terms of prediction targets. A striking lack of validated models emerged, as well as a general difficulty in reproducing many published studies, mainly due to the absence of the corresponding parameter lists. While deep learning seems promising for prediction applications, its superiority with respect to traditional methods has not been established; there is, instead, ample room for its application in the subfield of patient stratification. Finally, an open question remains on the role of new environmental and behavioural variables collected via novel, real-time sensors.

 

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The flail-arm syndrome: the influence of phenotypic features

Marta Gromicho, Miguel Oliveira Oliveira Santos, Susana Pinto, Michael Swash & Mamede De Carvalho

This research paper looked at a specific type of ALS called flail arm syndrome (FAS). FAS is characterized by weakness in the upper limbs, and it typically progresses slowly. The researchers studied the clinical features, progression, and survival of FAS patients, and they found that the presence or absence of upper motor neuron (UMN) signs at diagnosis was the most important factor in determining how long a patient would live.
The researchers found that the location of the weakness, whether it was in the distal muscles of the arms (the muscles closest to the fingers) or the proximal muscles of the arms (the muscles closest to the shoulders), did not affect the prognosis of FAS patients. This suggests that the most important factor in determining the prognosis of FAS is the severity of the disease, as indicated by the presence or absence of UMN signs.

 

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Trends in the diagnostic delay and pathway for amyotrophic lateral sclerosis patients across different countries

Catarina Falcão de Campos, Marta Gromicho, Hilmi Uysal, Julian Grosskreutz, Magdalena Kuzma-Kozakiewicz, Miguel Oliveira Santos, Susana Pinto, Susanne Petri, Michael Swash and Mamede de Carvalho

This paper investigated how long it takes to diagnose amyotrophic lateral sclerosis (ALS). The researchers examined data from more than 1,400 ALS patients from four different countries and discovered that the median diagnostic delay was 11 months. This means that it took people an average of 11 months from the time they noticed symptoms to being officially diagnosed with ALS.
The researchers discovered that several factors contributed to the diagnostic delay, including:
Symptom presentation: In the early stages of ALS, symptoms are frequently mild and nonspecific, making diagnosis difficult.
Referral to specialists: Many people with ALS are not initially referred to a neurologist, who is the specialist who can make a definitive diagnosis of ALS.
Testing: Electromyography (EMG) is a test that is used to measure electrical activity in muscles. EMG is very important for diagnosing ALS, but it is not always available or accessible.
The researchers propose that a specific diagnostic test for ALS, such as a biomarker, could help to shorten the diagnostic time. They also emphasize the importance of referring patients to a neurologist and performing an EMG to diagnose ALS early on.

 

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Sporadic Spinal-Onset Amyotrophic Lateral Sclerosis Associated with Myopathy in Three Unrelated Portuguese Patients

Miguel Oliveira Santos, Marta Gromicho, Ana Pronto-Laborinho and Mamede de Carvalho

This research paper explores the possible connection between amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects muscle control, and myopathy, a muscular condition that weakens muscles. The researchers describe three cases of ALS patients who also had myopathy, suggesting that there may be a link between these two conditions and that they may share some common causes.

 

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Respiratory phenotypes in amyotrophic lateral sclerosis as determined by respiratory questions on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised and their relation to respiratory tests

Susana Pinto, Miguel Oliveira Santos, Marta Gromicho, Michael Swash, Mamede de Carvalho

This research paper examined the association between respiratory symptoms and respiratory test results in patients with amyotrophic lateral sclerosis (ALS). The researchers found that there are three distinct groups of ALS patients based on their respiratory symptoms and test results. Patients with the most severe respiratory problems were more likely to need mechanical ventilation. Measuring the phrenic nerve amplitude may be helpful in identifying patients who are at risk of developing severe respiratory problems. Orthopnea is a severe symptom that should prompt NIV and early NIV promotes survival.

 

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Clinical characteristics in amyotrophic lateral sclerosis with Sub-Saharan Africa ancestry – A Portuguese hospital-based cohort study

Miguel Oliveira Santos, Marta Gromicho, Susana Pinto, Ana Pronto-Laborinho and Mamede de Carvalho

This research paper explores the characteristics of patients with amyotrophic lateral sclerosis (ALS) who originate from Sub-Saharan Africa (SSA) and are diagnosed and followed in a specialized ALS clinic in Portugal. Sub-Saharan African Amyotrophic Lateral Sclerosis (SAALS) is a distinct population with a younger onset age and a longer disease duration, but total survival is independent of SA ancestry. The researchers believe that the specialized ALS clinic in Portugal, with its access to respiratory care and riluzole, could explain the observed differences between their results and previous data from African ALS patients followed in their own countries. Improving access to healthcare for SAALS patients could help to improve their survival rates.

 

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Demographic changes in a large motor neuron disease cohort in Portugal: a 27 year experience

Inês Alves, Marta Gromicho, Miguel Oliveira Oliveira Santos, Susana Pinto, Ana Pronto-Laborinho, Michael Swash & Mamede De Carvalho

This research paper investigated the clinical and demographic characteristics of motor neuron disease (MND) patients over a 27-year period. The researchers found that the average age at onset of MND was increasing, diagnostic delay was decreasing, and the proportion of patients using respiratory support with noninvasive ventilation (NIV) was increasing. They also found that median survival was increasing for ALS patients with spinal onset.

The researchers suggest that these changes are likely due to improved comprehensive care for MND patients. They believe that early diagnosis and treatment, including the use of NIV, are contributing to the better outcomes seen in recent years.

The researchers’ findings are important for future studies exploring the impact of new treatments on MND patients.

 

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Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis

Clinical perspective, Peer-reviewed, Journal

Chio A, Moglia C, Canosa A, Manera U, Grassano M, Vasta R, Palumbo F, Gallone S, Brunetti M, Barberis M, De Marchi F, Dalgard C, Chia R, Mora G, Iazzolino B, Peotta L, Traynor BJ, Corrado L, Dalfonso S, Mazzini L, Calvo A.

In this paper we analysed, in a huge cohort of ALS patients belonging to the Piemonte and Valle d’Aosta registry, the copresence of pathogenic variants (a permanent change in the DNA sequence) in ALS related genes. We discovered that the 54% of patients carried at least one detrimental common variant or repeat expansion and the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity. Gene variants act as modifiers of ALS survival and can act on their own or in unison.

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Serum chloride as a respiratory failure marker in amyotrophic lateral sclerosis

Clinical perspective, Peer-reviewed, Journal

Manera U, Grassano M, Matteoni E, Bombaci A, Vasta R, Palumbo F, Torrieri MC, Cugnasco P, Moglia C, Canosa A, Chiò A, Calvo A.

To early recognise respiratory failure signs in ALS patients is of outstanding importance to precocious treat it with non-invasive ventilation. Many tests can be used to evaluate respiratory function in early phases: no one of them is considered unfailing, so a combination of them is usually performed in clinical practice. We identified than serum chloride, measured by a simple venous blood sampling, can add useful information by identifying patients that are starting to compensate acidosis due to nocturnal hypoventilation and the consequent increase of blood carbon dioxide, by increasing blood carbonate and expelling chloride in urines. Serum chloride is a cheap and widely diffuse that should be added to the initial standard examination in ALS patients.

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Amyotrophic lateral sclerosis regional progression intervals change according to time of involvement of different body regions

Clinical perspective, Peer-reviewed, Journal

Manera U, D’Ovidio F, Cabras S, Torrieri MC, Canosa A, Vasta R, Palumbo F, Grassano M, De Marchi F, Mazzini L, Mora G, Moglia C, Calvo A, Chiò A. 

ALS is one of the more heterogeneous neurological disease and the prediction of its progression is one of the most important topic in ALS research. Moreover, no study have previously evaluated the timing of progression in the different body regions that can be involved by the disease. To do that we collected a huge dataset comprehending all the ALS functional rating scale (ALSFRS-R) scores and, by performing different analysis, we discovered that functional impairment runs faster in the body regions involved later, suggesting a snowball-like behaviour of the disease.

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Mild Dysphagia Does Not Influence Survival in Ventilated Amyotrophic Lateral Sclerosis Patients

Miguel Oliveira Santos, Marta Gromicho, Susana Pinto, Michael Swash, Mamede de Carvalho

It is unknown if mild dysphagia affects survival of patients with amyotrophic lateral sclerosis (ALS) on continuous non-invasive ventilation (NIV). We often must discuss the pros and cons of gastrostomy in patients with NIV, but there is a lack of information on the issue. We, therefore, studied dysphagia as a survival predictor factor in patients with ALS already adapted to continuous NIV, using our collected data.
Our findings are relevant for decision-making processes concerning gastrostomy in this particular population.

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Motor Neuron Disease in Three Asymptomatic pVal50Met TTR Gene Carriers

Cláudia Santos Silva, Miguel Oliveira Santos, Marta Gromicho, Ana Pronto-Laborinho, Isabel Conceição & Mamede de Carvalho

This research paper explores the potential link between transthyretin (TTR) gene mutations and motor neuron disease (MND). TTR is a protein that plays a crucial role in protecting nerve cells from damage. Mutations in the TTR gene can cause the protein to malfunction and form amyloid deposits, which can lead to nerve damage and a condition called amyloidosis.
The researchers studied three patients with MND who were also found to carry the pVal50Met mutation of the TTR gene. This mutation is associated with a rare form of amyloidosis called hereditary amyloid transthyretin (ATTRv) amyloidosis. The researchers examined the patients’ clinical symptoms, imaging scans, cerebrospinal fluid tests, nerve conduction studies, and small fiber tests.
The researchers’ findings suggest that he TTR gene mutations may contribute to the development of MND in some patients.

 

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Delayed Diagnosis and Diagnostic Pathway of Amyotrophic Lateral Sclerosis Patients in Portugal: Where Can We Improve?

Catarina Falcão de Campos, Marta Gromicho, Hilmi Uysal, Julian Grosskreutz, Magdalena Kuzma-Kozakiewicz, Miguel Oliveira Santos, Susana Pinto, Susanne Petri, Michael Swash, Mamede de Carvalho

This paper discusses the challenges of diagnosing amyotrophic lateral sclerosis (ALS). The researchers found that people with spinal onset ALS, slower disease progression, cognitive symptoms at onset, and lower income were more likely to experience delays in diagnosis.
The authors also identified the referral process from non-neurologists to neurologists as a potential factor contributing to these delays. They suggest that early referral to a neurologist could help to expedite the diagnosis and improve outcomes for ALS patients.

 

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Baseline Machine Learning Approaches To Predict Amyotrophic Lateral Sclerosis Disease Progression

Trescato I., Guazzo A., Longato E., Hazizaj E., Roversi C., Tavazzi E., Vettoretti M., Di Camillo B.

The main goal of this study was to compare different methods for predicting the occurrence and timing of specific events in ALS, including the need for non-invasive ventilation, percutaneous endoscopic gastrostomy, and death. The study took place during the CLEF Challenge 2022, and the organizers provided two versions of datasets: the first comprised information collected only at the first visit after ALS diagnosis, while the second included all information collected during a 6-month follow-up starting from the first visit. Notably, regardless of the outcome predicted, the models including dynamic features improved model performance, highlighting the significance of the first 6 months of data for accurate predictions in fast-progressing diseases like ALS.

 

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iDPP@CLEF 2023: The Intelligent Disease Progression Prediction Challenge

Helena Aidos, Roberto Bergamaschi, Paola Cavalla, Adriano Chiò, Arianna Dagliati, Barbara Di Camillo, Mamede Alves de Carvalho, Nicola Ferro, Piero Fariselli, Jose Manuel García Dominguez, Sara C. Madeira & Eleonora Tavazzi

Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) are chronic diseases characterized by progressive or alternate impairment of neurological functions (motor, sensory, visual, cognitive). The goal of iDPP@CLEF Open Evaluation Challenge is to design and develop an evaluation infrastructure for AI algorithms able to: better describe disease mechanisms; stratify patients according to their phenotype assessed all over the disease evolution; predict disease progression in a probabilistic, time dependent fashion. iDPP@CLEF will continue in CLEF 2023, focusing on the prediction of MS progression and exploring whether pollution and environmental data can improve the prediction of ALS progression.

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