Upper motor neuron signs in primary lateral sclerosis and hereditary spastic paraplegia.

INTRODUCTION/AIMS: The frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP). METHODS: We retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration. We also compared PLS versus HSP patients. RESULTS: We included 34 PLS and 20 HSP patients, with a median symptom duration at first visit of 3.0 (interquartile range, IQR = 4.0) and 19.0 (IQR = 22.0) years, respectively. In PLS patients, hyperreflexia of upper (UL) (88.2%) and lower (LL) (91.2%) limbs, and LL spasticity (79.4%) were the most common findings. Spasticity of LL was significantly (p = .012) more frequent in LL-spinal onset subgroup, tongue spasticity in bulbar-onset subgroup (p = .021), and Hoffman sign in UL-spinal onset subgroup (p = .024). The PLS subgroup with shorter disease duration had a higher frequency of abnormal jaw jerk reflex (p = .037). Compared with HSP, PLS patients had a higher frequency of UL hyperreflexia (88.2% vs. 42.1%, p < .001) and UL spasticity (44.1% vs. 0.0%, p < .001). Asymmetric distribution of UMN signs was present in PLS and not in HSP. DISCUSSION: In PLS, UL UMN signs are nearly always present and UMN sign distribution appears to be associated with onset region. At first observation, bulbar involvement, asymmetrical distribution of UMN signs and UL spasticity may indicate PLS versus HSP.

Impact of diabetes mellitus on the respiratory function of amyotrophic lateral sclerosis patients.

BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain. METHODS: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2 mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t-test, χ2 , or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan-Meier analysis assessed survival. p < 0.05 was considered significant. RESULTS: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS-R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2 mean (p = 0.014). CONCLUSIONS: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups.

Erythrocytes' surface properties and stiffness predict survival and functional decline in ALS patients.

Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS-R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS-R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS-R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS.

Differential Expression of miRNAs in Amyotrophic Lateral Sclerosis Patients.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle atrophy and in later stages, death. Diagnosis has an average delay of 1 year after symptoms onset, which impairs early management. The identification of a specific disease biomarker could help decrease the diagnostic delay. MicroRNA (miRNA) expression levels have been proposed as ALS biomarkers, and altered function has been reported in ALS pathogenesis. The aim of this study was to assess the differential expression of plasma miRNAs in ALS patients and two control populations (healthy controls and ALS-mimic disorders). For that, 16 samples from each group were pooled, and then 1008 miRNAs were assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). From these, ten candidate miRNAs were selected and validated in 35 ALS patients, 16 ALS-mimic disorders controls and 15 healthy controls. We also assessed the same miRNAs in two different time points of disease progression. Although we were unable to determine a miRNA signature to use as disease or condition marker, we found that miR-7-2-3p, miR-26a-1-3p, miR-224-5p and miR-206 are good study candidates to understand the pathophysiology of ALS.

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

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive loss of motor neurons in the brain and spinal cord. The fact that ALS's disease course is highly heterogeneous, and its determinants not fully known, combined with ALS's relatively low prevalence, renders the successful application of artificial intelligence (AI) techniques particularly arduous. OBJECTIVE: This systematic review aims at identifying areas of agreement and unanswered questions regarding two notable applications of AI in ALS, namely the automatic, data-driven stratification of patients according to their phenotype, and the prediction of ALS progression. Differently from previous works, this review is focused on the methodological landscape of AI in ALS. METHODS: We conducted a systematic search of the Scopus and PubMed databases, looking for studies on data-driven stratification methods based on unsupervised techniques resulting in (A) automatic group discovery or (B) a transformation of the feature space allowing patient subgroups to be identified; and for studies on internally or externally validated methods for the prediction of ALS progression. We described the selected studies according to the following characteristics, when applicable: variables used, methodology, splitting criteria and number of groups, prediction outcomes, validation schemes, and metrics. RESULTS: Of the starting 1604 unique reports (2837 combined hits between Scopus and PubMed), 239 were selected for thorough screening, leading to the inclusion of 15 studies on patient stratification, 28 on prediction of ALS progression, and 6 on both stratification and prediction. In terms of variables used, most stratification and prediction studies included demographics and features derived from the ALSFRS or ALSFRS-R scores, which were also the main prediction targets. The most represented stratification methods were K-means, and hierarchical and expectation-maximisation clustering; while random forests, logistic regression, the Cox proportional hazard model, and various flavours of deep learning were the most widely used prediction methods. Predictive model validation was, albeit unexpectedly, quite rarely performed in absolute terms (leading to the exclusion of 78 eligible studies), with the overwhelming majority of included studies resorting to internal validation only. CONCLUSION: This systematic review 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.

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

Objective: Motor Neuron Diseases (MND) have a large clinical spectrum, being the most common amyotrophic lateral sclerosis (ALS) but there is significant clinical heterogeneity. Our goal was to investigate this heterogeneity and any potential changes during a long period. Methods: We performed a retrospective cohort study among a large Portuguese cohort of MND patients (n = 1550) and investigated changing patterns in clinical and demographic characteristics over the 27-year period of our database. With that aim, patients were divided into three 9-year groups according to the date of their first visit to our unit: P1, 1994-2002; P2, 2003-2011; P3, 2012-2020. Results: The overall cohort's clinical and demographic characteristics are consistent with clinical experience, but our findings point to gradual changes over time. Time pattern analysis revealed statistically significant differences in the distribution of clinical phenotypes, the average age of onset, diagnostic delay, the proportin of patients using respiratory support with noninvasive ventilation (NIV), time to NIV, and survival. Across time, in the overall cohort, we found an increasing age at onset (p = 0.029), a decrease of two months in diagnostic delay (p < 0.001) and a higher relative frequency of progressive muscular atrophy patients. For ALS patients with spinal onset, from P1 to P2, there was a more widespread (54.8% vs 69.4%, p = 0.005) and earlier (36.9 vs 27.2 months, p = 0.05) use of NIV and a noteworthy 13-month increase in median survival (p = 0.041). Conclusions: Our results probably reflect better comprehensive care, and they are relevant for future studies exploring the impact of new treatments on ALS patients.

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

This work proposes a new class of explainable prognostic models for longitudinal data classification using triclusters. A new temporally constrained triclustering algorithm, termed TCtriCluster, is proposed to comprehensively find informative temporal patterns common to a subset of patients in a subset of features (triclusters), and use them as discriminative features within a state-of-the-art classifier with guarantees of interpretability. The proposed approach further enhances prediction with the potentialities of model explainability by revealing clinically relevant disease progression patterns underlying prognostics, describing features used for classification. The proposed methodology is used in the Amyotrophic Lateral Sclerosis (ALS) Portuguese cohort (N = 1321), providing the first comprehensive assessment of the prognostic limits of five notable clinical endpoints: need for non-invasive ventilation (NIV); need for an auxiliary communication device; need for percutaneous endoscopic gastrostomy (PEG); need for a caregiver; and need for a wheelchair. Triclustering-based predictors outperform state-of-the-art alternatives, being able to predict the need for auxiliary communication device (within 180 days) and the need for PEG (within 90 days) with an AUC above 90%. The approach was validated in clinical practice, supporting healthcare professionals in understanding the link between the highly heterogeneous patterns of ALS disease progression and the prognosis.

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.

BACKGROUND AND PURPOSE: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). The association of respiratory test alterations with respiratory symptoms is unclear. METHODS: Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS-R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO2 mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors. RESULTS: We included 276 patients (153 men, onset age = 62.6 ± 11.0 years, disease duration = 13.0 ± 9.6 months, spinal onset in 182) with mean survival of 40.1 ± 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS-R subscores were significantly different (G1 > G2 > G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO2 mean. Independent predictors for G2 were MIP and SpO2 mean; for G3, the only independent predictor was PhrenAmpl. CONCLUSIONS: These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS-R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3.

Association of the practice of contact sports with the development of amyotrophic lateral sclerosis.

Objectives: High-intensity physical activity and sports prone to repetitive injuries of the cervical spine and head (when associated with vigorous practice) have been suggested as possible risk factors for amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the relationship between the practice of contact sports (boxing, hockey, football, rugby) and ALS. Methods: The study included 2247 individuals, 1326 patients and 921 controls from several European countries. Analysis of the effect of contact sports on ALS was conducted in male participants only, as very few women practiced contact sports. Logistic regression models were used with the response variable as the presence or absence of ALS, with α = 0.05 significance level. Results: A relationship between the practice of contact sports and ALS was found, with those practicing contact sports having 76% higher odds of an ALS diagnosis (OR = 1.76, p = 0.001). In addition, univariate analyses for age (higher risk for older people, p < 0.001), smoking status (higher risk for ex-smokers, p = 0.022) and tobacco exposure (higher risk for more exposure, p = 0.038) also indicated that these variables are risk factors for ALS. In multivariate models, in addition to age, the interaction term between practice of contact sports and tobacco exposure was still significant (p = 0.03). Conclusions: This is one of the largest studies on the role of contact sport in ALS development. Our results support the existence of a relationship between the practice of sports with repetitive trauma at the level of the cervical spine and head, and ALS. This risk appears to be enhanced by tobacco exposure.

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

Amyotrophic lateral sclerosis (ALS) and myopathy have been already described as part of a common genetic syndrome called multisystem proteinopathy. They may occur together or not, and can be associated with other clinical features such as frontotemporal dementia and Paget's bone disease. In addition, primary skeletal muscle involvement has been also reported in inherited forms of lower motor neuron disease, in spinal-bulbar muscular atrophy and in spinal muscular atrophy. We aim to characterize three sporadic, spinal-onset ALS patients, one with a concurrent non-specific myopathy, and two with a previous diagnosis of myopathy before upper and lower motor neuron signs emerged. Perhaps our sporadic ALS cases associated with myopathy share a common, but still unknown, pathogenic background. These cases raise the paradigm of a possible interplay between skeletal muscle degeneration and motor neuron damage.

The flail-arm syndrome: the influence of phenotypic features.

Objective: The flail-arm syndrome (FAS), one of the Amyotrophic lateral sclerosis (ALS) phenotypes, is characterized by slow progression and predominantly lower motor neuron (LMN) involvement with proximal upper limb (UL) weakness. We aim to characterize the clinical features, progression and survival of FAS associated with distal or proximal onset and presence or absence of upper motor neuron signs (UMN) signs at diagnosis. Methods: Data from 704 ALS patients was analyzed. Of the 190 patients with UL onset; 134 were excluded as not respecting the published criteria for FAS. The included patients were divided into four groups according to distal/proximal onset and presence/absence of UMN signs. Results: 56 FAS patients (8% of the population), median age at onset 59.9 years (Q1/Q3, 50.3-68.1), 75% men, were studied. Distal onset with UMN signs occurred in 37.5%, distal onset without UMN signs in 28.6%, proximal onset with UMN signs in 8.9% and proximal onset without UMN signs in 25%. Age of onset, sex, fasciculations at onset, diagnostic delay, progression rate, time to respiratory involvement and survival were similar among the four groups. Sex ratio was more balanced in patients with UMN signs (p = 0.032) and survival was shorter (69.5 months, 95% CI: 55.4-110.4 vs 152.6 months, 95% CI: 69.0-177.3; p = 0.035). The Cox regression identified rate of progression (p < 0.001) and UMN signs (p = 0.003) as independent predictors of shorter survival. Conclusions: Distal or proximal onset had no influence on clinical characteristics and prognosis but UMN signs at diagnosis are a negative prognostic predictor.

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

Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS). Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions. Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 ± 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X2=42.0, p < 0.001) and of survival (X2=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 ± 5.7mo and to a 3rd region 6.1 ± 8.7mo. Different patterns of spread had no impact on survival. Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS.

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

Longitudinal cohort studies to study disease progression generally combine temporal features produced under periodic assessments (clinical follow-up) with static features associated with single-time assessments, genetic, psychophysiological, and demographic profiles. Subspace clustering, including biclustering and triclustering stances, enables the discovery of local and discriminative patterns from such multidimensional cohort data. These patterns, highly interpretable, are relevant to identifying groups of patients with similar traits or progression patterns. Despite their potential, their use for improving predictive tasks in clinical domains remains unexplored. In this work, we propose to learn predictive models from static and temporal data using discriminative patterns, obtained via biclustering and triclustering, as features within a state-of-the-art classifier, thus enhancing model interpretation. triCluster is extended to find time-contiguous triclusters in temporal data (temporal patterns) and a biclustering algorithm to discover coherent patterns in static data. The transformed data space, composed of bicluster and tricluster features, capture local and cross-variable associations with discriminative power, yielding unique statistical properties of interest. As a case study, we applied our methodology to follow-up data from Portuguese patients with Amyotrophic Lateral Sclerosis (ALS) to predict the need for non-invasive ventilation (NIV) since the last appointment. The results showed that, in general, our methodology outperformed baseline results using the original features. Furthermore, the bicluster/tricluster-based patterns used by the classifier can be used by clinicians to understand the models by highlighting relevant prognostic patterns.

Analysis of routine blood parameters in patients with amyotrophic lateral sclerosis and evaluation of a possible correlation with disease progression-a multicenter study.

Objective: Amyotrophic lateral sclerosis (ALS) pathogenesis is still unclear, its course is considerably variable, and prognosis is hard to determine. Despite much research, there is still a lack of easily accessible markers predicting prognosis. We investigated routine blood parameters in ALS patients regarding correlations with disease severity, progression rate, and survival. Additionally, we analyzed disease and patients' characteristics relating to baseline blood parameter levels. Methods: We analyzed creatine kinase (CK), albumin (ALB), creatinine (CREA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels around time of diagnosis in 1,084 ALS patients. We carried out linear regression analyses including disease and patients' characteristics with each blood parameter to detect correlations with them. Linear regression models were performed for ALSFRS-R at study entry, its retrospectively defined rate of decay and prospectively collected progression rate. Different survival analysis methods were used to examine associations between blood parameters and survival. Results: We found higher CK (p-value 0.001), ALB (p-value <0.001), CREA (p-value <0.001), and HDL levels (p-value 0.044) at time of diagnosis being associated with better functional status according to ALSFRS-R scores at study entry. Additionally, higher CREA levels were associated with lower risk of death (p-value 0.003). Conclusions: Our results indicate potential of CK, ALB, CREA, and HDL as disease severity or progression markers, and may also provide clues to ALS pathogenesis. However, these values are highly dependent on other variables, and further careful, longitudinal analyses will be necessary to prove the relevance of our findings.

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

BACKGROUND: Some amyotrophic lateral sclerosis (ALS) patients on continuous non-invasive ventilation (NIV) develop dysphagia demanding a clinical decision regarding gastrostomy. MATERIAL AND METHODS: We have analyzed a cohort of seventy-four ALS patients dependent on continuous NIV (>22 h/day) and without feeding tube. RESULTS: Three patients underwent to gastrostomy due to dysphagia progression. The other patients were categorized in two groups according to question 3 ("swallowing") of the ALSFRS-R scale: group 1 (G1), score = 4 (normal), and group 2 (G2), score = 3 or 2 (mild-moderate dysphagia). G2 included 29 (40.8%) patients. Survival was similar in G1 and G2 (p = 0.12). Disease duration (p < 0.0001) and ALSFRS-R progression rate (p = 0.008) at NIV >22 h/day were predictors for survival in G1, but not for G2. Gender, onset-region, and age at NIV >22 h/day did not influence survival. CONCLUSIONS: Our findings are relevant when discussing gastrostomy with these patients.

Thyroid dysfunction in Portuguese amyotrophic lateral sclerosis patients.

INTRODUCTION: Thyroid hormones influence neuromuscular function, and it has been thought that this might contribute to degeneration of motor neurons. METHODS: We used case-control methods to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) in ALS patients followed in our centre, between 2015 and 2020. Data from patients with neuromuscular disorders not derived from thyroid dysfunction, followed within the same time frame, were used as controls. Thyroid dysfunction was defined by previous thyroid replacement medication managed by an endocrinologist. We used odds ratios (OR) with a 95% confidence interval (CI) to compare 579 ALS patients and 415 age-gender-matched disease controls. Additionally, we provide a summarized review of the literature. RESULTS: Hypothyroidism (prevalence of 5.0 versus 8.6%; OR = 0.56, 95% CI 0.34-0.92, p = 0.023), hyperthyroidism (prevalence of 0.3 versus 1.2%; OR = 0.28, 95% CI 0.06-1.47, p = 0.134) and overall thyroid dysfunction (prevalence of 5.4 versus 9.9%; OR = 0.52, 95% CI 0.32-0.84, p = 0.015) were less prevalent in ALS patients than in controls, but similar to the national epidemiological data for thyroid disease. Our data are in line with the findings of most previous studies. CONCLUSIONS: We conclude that thyroid dysfunction is not associated with ALS.

Dynamic Bayesian networks for stratification of disease progression in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Progression rate is quite variable in amyotrophic lateral sclerosis (ALS); thus, tools for profiling disease progression are essential for timely interventions. The objective was to apply dynamic Bayesian networks (DBNs) to establish the influence of clinical and demographic variables on disease progression rate. METHODS: In all, 664 ALS patients from our database were included stratified into slow (SP), average (AP) and fast (FP) progressors, according to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) rate of decay. The sdtDBN framework was used, a machine learning model which learnt optimal DBNs with both static (gender, age at onset, onset region, body mass index, disease duration at entry, familial history, revised El Escorial criteria and C9orf72) and dynamic (ALSFRS-R scores and sub-scores, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and phrenic amplitude) variables. RESULTS: Disease duration and body mass index at diagnosis are the foremost influences amongst static variables. Disease duration is the variable that better discriminates the three groups. Maximum expiratory pressure is the respiratory test with prevalent influence on all groups. ALSFRS score has a higher influence on FP, but lower on AP and SP. The bulbar sub-score has considerable influence on FP but limited on SP. Limb function has a more decisive influence on AP and SP. The respiratory sub-score has little influence in all groups. ALSFRS-R questions 1 (speech) and 9 (climbing stairs) are the most influential in FP and SP, respectively. CONCLUSIONS: The sdtDBN analysis identified five variables, easily obtained during clinical evaluation, which are the most influential for each progression group. This insightful information may help to improve prognosis and care.

Motor neuron disease in three asymptomatic pVal50Met TTR gene carriers.

We describe three unrelated patients with sporadic motor neuron disease (MND) and hereditary amyloid transthyretin (ATTRv) amyloidosis family history, who were asymptomatic carriers of the pVal50Met mutation of transthyretin (TTR) gene. Patients 1 and 2 were a 43-year-old man with a spinal-onset of ALS and a 37-year-old woman with a bulbar-onset of ALS, who died due to respiratory complications five and two years after disease onset, respectively. Patient 3 is a 52-year-old woman, with a two-year history of a probable primary lateral sclerosis, and a frontotemporal dysfunction. Imaging, cerebrospinal fluid (CSF) and nerve conduction and small fiber tests were normal in all. Genetic testing for ALS was negative in the two patients tested. Previous studies in MND patients have identified reduced TTR levels in CSF and neuronal gene overexpression, suggesting a neuroprotective role of TTR. The association of MND in patients with TTR gene mutations has not yet been described.