Cohort Of Amyotrophic Lateral Sclerosis Patients Research Articles

Takotsubo syndrome in a Sardinian amyotrophic lateral sclerosis cohort.

Amyotrophic lateral sclerosis (ALS) is known to be associated with varying degrees of autonomic and cardiovascular dysfunction. Recent case reports showed that ALS may be linked to Takotsubo syndrome (TTS). We assessed the frequency of TTS in an incident ALS cohort from Sardinia, Italy, and investigated the relationship of TTS with ALS course. We retrospectively examined a 10-year (2010-2019) incident cohort of ALS patients of Sardinian ancestry, reported TTS frequency and patients' clinical characteristics. Following, we checked for TTS among patients with ALS onset after 2019 and focused on the same features as for the incident cohort. Our incident cohort included 344 ALS patients and 5 of them (1.45%) developed TTS. All were female and their median onset age was 71.5years (IQR 62.75-77). Two patients had spinal and three bulbar onset, though all patients had bulbar involvement and were at an advanced stage of disease (ALSFRS ≤ 25, King's ≥ 3) at TTS diagnosis. We identified a potential TTS trigger in three patients (hospitalization for PEG placement, pneumonia). Among patients who had ALS onset after 2019, we identified a further TTS case and described it. TTS is not a rare condition in ALS. Female sex, bulbar involvement, and later age of disease onset may be important risk factors for developing this cardiac condition and a physical or psychological trigger is often observed. Despite autonomic dysfunction in ALS has been already demonstrated, the precise physiopathological mechanism underlying TTS needs to be further clarified.

Factors associated with Edinburgh Cognitive and Behavioural ALS Screen (ECAS) alteration at time of diagnosis, in amyotrophic lateral sclerosis

BackgroundEdinburgh Cognitive and Behavioral ALS Screen (ECAS) is a validated assessment designed to screen cognitive functions and behavioral disorders in amyotrophic lateral sclerosis (ALS). Objective of this study is to determine the factors associated with ECAS impairment in a cohort of ALS patients without a co-morbid diagnosis of dementia, at the time of diagnosis. MethodsWe enrolled 71 non-demented ALS patient. We collected clinical and demographic data, ALS familiarity, analysis of the most commonly mutated genes in ALS, ALS Milano Torino Staging System and ALS Functional Rate Scale revised scores, progression rate; finally, we recorded whether symptoms onset involved spinal or bulbar area. The alteration of the ECAS was estimated based on age and education-adjusted-validated cut off for each of the items included in ECAS. A multivariable regression analysis was done. ResultsThe significant determinants of ECAS alterations were: bulbar onset in both ALS-specific test and total ECAS score; bulbar onset and familiarity in ALS-non-specific test; finally, familiarity and diagnosis delay in ALS-behavioral test. All the subjects carrying C9orf72 mutations had alteration of both total ECAS score and ALS-specific tests. DiscussionAt diagnosis, bulbar-onset ALS, family history, diagnosis delay and C9orf72 hexanucleotide repeat expansion may contribute to impairment of ECAS.

Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons

BackgroundSeveral studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n 〈100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS. AimsTo investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment. Material and methodsThe strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern. ResultsMuscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee. ConclusionsThe extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.

High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants.

While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls. All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included. Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse. Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.

Electrodiagnostic findings in amyotrophic lateral sclerosis: Variation with region of onset and utility of thoracic paraspinal muscle examination.

Limited data exist regarding variation of electrodiagnostic (EDX) findings in amyotrophic lateral sclerosis (ALS) patients with different onset regions and specificity of thoracic paraspinal muscle (TPSP) examination for confirming a diagnosis of ALS. We aimed to demonstrate the variation of EDX features and characterize the utility of TPSP muscle examination in the electrodiagnosis of ALS. This is a retrospective study of a large cohort of ALS patients who had a comprehensive EDX evaluation. The study included 448 patients; all fulfilled the Gold Coast criteria for ALS. The average age at the time of EDX study was 64 years, and 41.1% were women. The onset region was identified as follows: bulbar (N = 149), cervical (N = 127), lumbosacral (N = 162), and other (N = 10). In contrast to limb onset, bulbar-onset patients more frequently demonstrated a pattern of normal or near normal needle electromyography (EMG) (p < .0001) and less frequently had abnormalities on EMG of TPSP (p = .002). Clinical or EDX diagnosis of sensory polyneuropathy was present in 12.6% patients, more frequently in the lumbosacral onset subgroup (p < .03). EMG showed active denervation in 9.6% and chronic denervation in 59% of craniobulbar muscles examined, without observed difference among different onset regions. TPSP showed higher frequencies of active and chronic denervation in ALS than a group of patients with non-ALS neuromuscular disorders. EDX features may differ among ALS patients of different onset regions. TPSP EMG is highly useful in differentiating ALS from non-ALS neuromuscular disorders while the yield of craniobulbar muscles, especially for active denervation, is low.

Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. In this monocentric retrospective study, clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups regarding their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). A comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then, Cox regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p < 0.0001) and with vital forced capacity (p = 0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients' survival.

High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis

BackgroundUric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients.MethodsWe enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007–2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT).ResultsOut of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (μmol/L; ALS-INT, 289.7 ± 75.5 μmol/L; ALS-FTD, 271.8 ± 74.9 μmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01–1.43; p = 0.038) in binary logistic regression.ConclusionsWe found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.

Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients

AimsNeuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity.Subjects and MethodsBlood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score).ResultsAge at onset was 65y (58–71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48–78) in PLS and 56y (44–68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158–360] vs. Controls = 174[113–240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels.ConclusionsWe show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis.

Serum chloride as a respiratory failure marker in amyotrophic lateral sclerosis.

Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS) and occurs with great variability among patients according to different phenotypic features. Early predictors of respiratory failure in ALS are important to start non-invasive ventilation (NIV). Venous serum chloride values correlate with carbonate (HCO3-) blood levels and reflect metabolic compensation of respiratory acidosis. Despite its wide availability and low cost, few data on serum chloride as a prognostic marker exist in ALS literature. In the present study, we evaluated serum chloride values at diagnosis as prognostic biomarkers for overall survival and NIV adaptation in a retrospective center-based cohort of ALS patients. We collected all ALS patients with serum chloride assessment at diagnosis, identified through the Piemonte and Valle d'Aosta Register for ALS, evaluating the correlations among serum chloride, clinical features, and other serum biomarkers. Thereafter, time-to-event analysis was modeled to predict overall survival and NIV start. We found a significant correlation between serum chloride and inflammatory status markers, serum sodium, forced vital capacity (FVC), ALS functional rating scale-revised (ALSFRS-R) item 10 and 11, age at diagnosis, and weight loss. Time-to-event analysis confirmed both in univariate analysis and after multiple confounders' adjustment that serum chloride value at diagnosis significantly influenced survival and time to NIV start. According to our analysis, based on a large ALS cohort, we found that serum chloride analyzed at diagnosis is a low-cost marker of impending respiratory decompensation. In our opinion, it should be added among the serum prognostic biomarkers that are able to stratify patients into different prognostic categories even when performed in the early phases of the disease.

Potential role of vitamin D levels in amyotrophic lateral sclerosis cognitive impairment

Cognitive impairment (CI) is common in amyotrophic lateral sclerosis (ALS): a keystone is identifying factors that could potentially modify the CI course. In recent years, vitamin D is becoming a potential modificatory factor for CI in many neurological disorders. This study aimed to highlight if vitamin D deficiency correlated with CI and clinical features in a cohort of ALS patients. We included 55 ALS patients with a neuropsychological evaluation (classified with the Strong Criteria) and a vitamin D dosage at the diagnosis. We also reviewed medical records and completed data for medical history, physical and neurological examination, and functional scales. At the diagnosis, 30 patients (54%) had CI. Most patients (82%) displayed low vitamin D levels (19.87 ± 9.80 ng/ml). Comparing the vitamin D level between patients with and without CI, we observed significantly lower values in the first group (15.8 ± 8.2 vs. 22.0 ± 9.7 ng/ml, p: 0.04). In the spinal female subgroup (n = 15), we found an inverse correlation between vitamin D and bizarreness score in the cognitive estimates test (r = 0.58; p: 0.04) and a positive correlation with the Corrected Raven’s Standard Progressive Matrices (r = 0.53, p: 0.04). Conversely, in the bulbar female group, we observed a correlation with the corrected direct span (r = 0.84, p: 0.03). With the log-rank survival analysis, we found that the patients with vitamin D < 10 ng/ml had a shorter disease duration (Chi: 5.78, p: 0.02). Our results indicate that levels of vitamin D can influence the cognitive status of people living with ALS and that severe deficits might be an adverse prognostic survival factor.

Evaluation of arterial blood gas parameters as prognostic markers in amyotrophic lateral sclerosis.

Forced vital capacity (FVC) remains difficult to determine for some patients suffering from amyotrophic lateral sclerosis (ALS) due to the rapid progression of the disease. Arterial blood gas (ABG) parameters could represent a valuable alternative. The aim of this study was therefore to evaluate the correlation between ABG parameters and FVC, along with the prognostic ability of ABG parameters, in a large cohort of ALS patients. ALS patients (n=302) with FVC and ABG parameters available at diagnosis were included. Correlations between ABG parameters and FVC were evaluated. Cox regression was then carried out to determine the association of each parameter (ABG and clinical data) with survival. Finally, receiver operating characteristic (ROC) curves were built to predict the survival of ALS. Bicarbonates (HCO3 - ), oxygen partial pressure (pO2 ), carbon dioxide partial pressure (pCO2 ), base excess (BE), oxygen saturation and oxyhemoglobin were significantly correlated with FVC both in patients with spinal or bulbar onset. Univariate Cox regression showed that HCO3 - and BE were associated with survival but only in spinal forms. ABG parameters predicted the survival of ALS with a similar performance to FVC, HCO3 - being the parameter with the highest area under the curve. Our results suggest that there is an interest in conducting a longitudinal evaluation throughout disease progression to confirm the equal performances of FVC and ABG. This study highlights the benefits of performing ABG analysis that could be used as an interesting alternative to FVC when spirometry cannot be performed.

NOTCH2NLC GGC repeats are not expanded in Italian amyotrophic lateral sclerosis patients

Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been recently reported in 0.7% of sporadic ALS patients from mainland China. This finding was not confirmed in an ALS cohort of subjects from Taiwan. As the involvement of expanded NOTCH2NLC alleles in ALS is debated, we addressed this point by evaluating NOTCH2NLC repeat expansions in an Italian cohort of ALS patients. A screening analysis of NOTCH2NLC GGC repeats was performed by repeat-primed polymerase chain reaction (RP-PCR) in a cohort of 385 probable/definite ALS Italian patients. Mean age at onset was 60.5 years (SD 13.7), and 60.9% were males. Sporadic cases were 357 (92.7%), and most patients had a spinal onset (71.8%). None of our patients showed the typical sawtooth tail pattern on RP-PCR, thus excluding abnormal repeat expansion in NOTCH2NLC. Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS.

At-home noninvasive ventilation initiation with telemonitoring in amyotrophic lateral sclerosis patients: a retrospective study.

Noninvasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. NIV initiation is mostly conducted at hospital, but a recurrent lack of hospital beds led to the necessity of exploring an at-home initiation process. Here, we report data from our NIV initiation cohort of ALS patients. Could our at-home NIV initiation process with telemonitoring in ALS patients be an efficient solution for adherence and nocturnal hypoxaemia correction? We performed a retrospective analysis of data collected from 265 ALS patients treated at the Bordeaux ALS Centre for whom NIV initiation was carried out between September 2017 and June 2021, with two modalities: at-home initiation or in-hospital initiation. The primary outcome was adherence to NIV at 30 days. The secondary outcome was at-home NIV initiation process efficiency of nocturnal hypoxaemia correction. At 30 days, NIV adherence (mean >4 h·day-1) was 66% of the total population, 70% of the at-home NIV initiation subgroup and 52% of the in-hospital NIV initiation subgroup. Nocturnal hypoxaemia correction was observed in 79% of adherent patients in the at-home NIV initiation subgroup. Mean delay of NIV prescription and at-home NIV initiation was 8.7 days (+/-6.5) versus 29.5 days in hospital. Our study shows that our at-home NIV initiation process in ALS patients is a good option to provide rapid access to NIV with good adherence and efficiency. Further literature on the benefits of at-home NIV initiation is welcomed, especially to evaluate long-term efficiency and global cost analysis.

Stereological and electrophysiological evaluation of autonomic involvement in amyotrophic lateral sclerosis

ObjectivePrevious studies have identified autonomic dysfunction in amyotrophic lateral sclerosis (ALS) using mostly neurophysiological techniques. In this study, stereological evaluation of autonomic fibers and sweat glands has been performed to identify structural evidence of autonomic denervation in patients with ALS. MethodsIn this study, 29 ALS patients were compared to 29 controls using COMPASS-31 questionnaire, sympathetic skin response (SSR), and heart rate variability (HRV) at rest. From the same cohorts, 20 ALS patients and 15 controls were further evaluated using staining of autonomic nerve fibers and sweat glands in skin biopsies. SSR and resting HRV were repeated in the ALS patient cohort one year later. ResultsCOMPASS-31 total score, gastrointestinal- and urinary-sub scores were higher in ALS patients than controls (P = 0.004, P = 0.005, and P = 0.049, respectively). In the ALS patient cohort, SSR amplitudes in hands and feet were lower than in controls (P<0.0001 and P = 0.0009, respectively), but there was no difference in resting HRV (P>0.05). While there was no change in nerve fibers innervating sweat glands, their density was lower in ALS patients than controls, and semi-quantitative analysis also showed structural damage (P = 0.02 and P = 0.001, respectively). SSR and resting HRV of ALS patients remained stable during the one-year follow-up period (P>0.05). DiscussionSupporting abnormal neurophysiological tests, stereological analysis revealed direct evidence of autonomic denervation in ALS patients. However, the degenerative process in autonomic nerve fibers is relatively slow, compared to the rate of motor neuron degeneration in this condition.

Markers of cognitive resilience and a framework for investigating clinical heterogeneity in ALS†.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Despite the unifying pathological hallmark of TDP-43 proteinopathy, ALS is clinically a highly heterogeneous disease, and little is known about the underlying mechanisms driving this phenotypic diversity. In a recent issue of The Journal of Pathology, Banerjee, Elliott et al use region-specific transcriptomic profiling in postmortem brains from a deeply phenotyped clinical cohort of ALS patients to detect molecular signatures differentiating cognitively affected and unaffected patients. They identified differential expression of specific genes, including upregulation of pro-inflammatory IL-6 in the cognitively affected group and anti-inflammatory IL-1 in the cognitively unaffected group. They then utilised BaseScope™ in situ hybridisation and immunohistochemistry to validate upregulation of NLRP3, an activator of the inflammasome, in the cognitively affected group, and upregulation of SIRT2, an inhibitor of NLRP3, in the cognitively unaffected group. In summary, Banerjee, Elliott et al demonstrate the usefulness of combining a well-curated clinical cohort with transcriptomic analysis of pathological samples to identify a perturbed pathway (e.g., the inflammasome), offering opportunities for novel therapeutic targets in ALS. © 2022 The Pathological Society of Great Britain and Ireland.

Eye Movement Abnormalities in Amyotrophic Lateral Sclerosis in a Tunisian Cohort

ABSTRACT Few studies have reported abnormal ocular movements in cases of amyotrophic lateral sclerosis (ALS) and their link with other disease features. Our study aimed to describe and analyse eye movement abnormalities in ALS patients. Specifically, we set out to investigate the correlation between non-motor signs and oculomotor impairment in order to understand the pathogenesis of the disease. All ALS patients seen from 2018 to 2020 in the department of Neurology of Razi hospital underwent the recording of saccadic eye movements. Results were compared with healthy controls. Sixty-two patients were included. Altered saccadic eye movements (72.6%) correlated with tongue atrophy and bladder dysfunction. The most common finding was altered smooth pursuit (56.5%), which showed correlation with bladder dysfunction and altered frontal assessment battery (FAB) scores. Prolonged latencies of horizontal saccades (34%) correlated with sensory and extrapyramidal signs. Our study is the first to examine the characteristics of eye movements in a large African cohort of ALS patients and to show correlations with extra-motor clinical signs. Our findings showed extra-motor cortex dysfunction in ALS with greater frequency of eye movement abnormalities in comparison with previous studies. Altered horizontal pursuit, the core abnormality, confirmed the extension of the neurodegenerative process to the frontal and prefrontal cortices. Prolonged horizontal saccade latencies reflect mainly the involvement of the parietal eye field. Anti-saccadic abnormalities were the least common finding and showed, paradoxically, no link with executive dysfunction.

Segmental alterations of the corpus callosum in motor neuron disease: A DTI and texture analysis in 575 patients

IntroductionWithin the core neuroimaging signature of amyotrophic lateral sclerosis (ALS), the corpus callosum (CC) is increasingly recognized as a consistent feature. The aim of this study was to investigate the sensitivity and specificity of the microstructural segmental CC morphology, assessed by diffusion tensor imaging (DTI) and high-resolution T1-weighted (T1w) imaging, in a large cohort of ALS patients including different clinical phenotypes. MethodsIn a single-centre study, 575 patients with ALS (classical phenotype, N = 432; restricted phenotypes primary lateral sclerosis (PLS) N = 55, flail arm syndrome (FAS) N = 45, progressive bulbar palsy (PBP) N = 22, lower motor neuron disease (LMND) N = 21) and 112 healthy controls underwent multiparametric MRI, i.e. volume-rendering T1w scans and DTI. Tract-based fractional anisotropy statistics (TFAS) was applied to callosal tracts of CC areas I-V, identified from DTI data (tract-of-interest (TOI) analysis), and texture analysis was applied to T1w data. In order to further specify the callosal alterations, a support vector machine (SVM) algorithm was used to discriminate between motor neuron disease patients and controls. ResultsThe analysis of white matter integrity revealed predominantly FA reductions for tracts of the callosal areas I, II, and III (with highest reductions in callosal area III) for all ALS patients and separately for each phenotype when compared to controls; texture analysis demonstrated significant alterations of the parameters entropy and homogeneity for ALS patients and all phenotypes for the CC areas I, II, and III (with again highest reductions in callosal area III) compared to controls. With SVM applied on multiparametric callosal parameters of area III, a separation of all ALS patients including phenotypes from controls with 72% sensitivity and 73% specificity was achieved. These results for callosal area III parameters could be improved by an SVM of six multiparametric callosal parameters of areas I, II, and III, achieving a separation of all ALS patients including phenotypes from controls with 84% sensitivity and 85% specificity. DiscussionThe multiparametric MRI texture and DTI analysis demonstrated substantial alterations of the frontal and central CC with most significant alterations in callosal area III (motor segment) in ALS and separately in all investigated phenotypes (PLS, FAS, PBP, LMND) in comparison to controls, while no significant differences were observed between ALS and its phenotypes. The combination of the texture and the DTI parameters in an unbiased SVM-based approach might contribute as a neuroimaging marker for the assessment of the CC in ALS, including subtypes.

Medulla oblongata volume as a promising predictor of survival in amyotrophic lateral sclerosis

BackgroundUnconventional magnetic resonance imaging studies of the brainstem have recently acquired a growing interest in amyotrophic lateral sclerosis (ALS) pathology since they provide a unique opportunity to evaluate motor tract degeneration and bulbar lower motor neuron involvement. The aim of this study was to investigate the role of brainstem structures as accurate biomarkers of disease severity and predictors of survival. Materials and MethodsA total of 60 ALS patients and 30 healthy controls subjects (CS) were recruited in this study. Patients were divided in two subgroups according to the onset of the disease: 42 spinal (S-ALS) and 18 bulbar (B-ALS). All subjects underwent 3D-structural MRI. Brainstem volume both of the entire cohort of ALS patients and S-ALS and B-ALS onset were compared with those of CS. In addition the two ALS subgroups were tested for differences in brainstem volumes.Volumetric, vertex-wise, and voxel-based approaches were implemented to assess correlations between MR structural features and clinical characteristics expressed as ALSFRS-r and its bulbar (ALSFSR-r-B) and spinal subscores (ALSFSR-r-S). ROC curves were performed to test the accuracy of midbrain, pons, and medulla oblongata volumes able to discriminate patients dichotomized into long and short survivors by using Two-Steps cluster analysis. Univariate and multivariate survival analyses were carried out to test the prognostic role of brainstem structures’ volume, trichotomized by applying a k-means clustering algorithm. ResultsBoth the entire cohort of ALS patients and B-ALS and S-ALS showed significant lower volumes of both medulla oblongata and pons compared to CS. Furthermore, B-ALS showed a significant lower volume of medulla oblongata, compared to S-ALS. Lower score of ALSFRS-r correlated to atrophy in the anterior compartment of midbrain, pons, and medulla oblongata, as well as in the posterior portion of only this latter region. ALSFSR-r-S positively correlated with shape deformation and density reduction of the anterior portion of the entire brainstem, along the corticospinal tracts. ALSFSR-r-B instead showed a positive correlation with shape deformation of the floor of the fourth ventricle in the medulla oblongata and the crus cerebri in the midbrain. Only medulla oblongata volume demonstrated a significant accuracy to discriminate long and short survivors ALS patients (ROC AUC 0.76, p < 0.001). Univariate and multivariate analysis confirmed the survival predictive role of the medulla oblongata (log rank test p: 0.003). DiscussionsOur findings suggest that brainstem volume may reflect the impairment of corticospinal and corticobulbar tracts as well as lower bulbar motor neurons. Furthermore, medulla oblongata could be used as an early predictor of survival in ALS patients.

Respiratory domain of ALSFRS-R scale increases arterial blood gas analysis’ sensitivity in assessing pulmonary function in amyotrophic lateral sclerosis

Spirometry is commonly used to monitor respiratory function in Amyotrophic Lateral Sclerosis (ALS). However, its use is poorly accurate in patients with bulbar or cognitive impairment. Arterial blood gas analysis (ABG) correlates moderately with forced vital capacity (FVC). We aimed at investigating if the assessment of the ALSFRS-r respiratory items (10 and 11) increases the correlation between ABG and FVC in a cohort of ALS patients.

Progression of Oropharyngeal Dysphagia in Amyotrophic Lateral Sclerosis: A Retrospective Cohort Study

Little is known regarding the optimal timing of dysphagia assessment and PEG indication in amyotrophic lateral sclerosis (ALS). The study aims to investigate the progression of dysphagia in a cohort of ALS patients and to analyse whether there are variables linked to a faster progression of dysphagia and faster indication of PEG placement. A retrospective cohort study in 108 individuals with ALS. Fiberoptic endoscopic evaluation of swallowing was performed 6 monthly until PEG indication or death. Dysphagia severity and PEG indication were assessed using Penetration Aspiration Scale. Progression Index (PI) analysed the risk of disease progression (fast/slow) in relation to dysphagia onset and PEG indication. Patients were grouped based on ALS onset and PI. Person-time incidence rates were computed considering dysphagia onset and PEG indication from ALS symptoms during the entire observation period and have been reported as monthly and 6-month rates. Cox regression survival analysis assessed dysphagia and PEG risk factors depending on onset. Person-time incidence rates of dysphagia progression and PEG risk were increased based on type of ALS onset and PI. Patients with a fast progressing disease and with bulbar onset (BO) show statistically significant increased risk of dysphagia (BO 178.10% hazard ratio (HR) = 2.781 P < 0.01; fast 181.10% HR 2.811 P < 0.01). Regarding PEG risk, fast patients and patients with BO had a statistically significant increased risk (fast 147.40% HR 2.474 P < 0.01, BO 165.40% HR 2.654 P < 0.01). Fast PI predicts the likelihood of faster progression of dysphagia and PEG indication and should be included in multidisciplinary assessments and considered in the design of future guidelines regarding dysphagia management in ALS patients.Level of Evidence Level IV.