Amyotrophic Lateral Sclerosis Subgroups Research Articles

Distinct Longitudinal Changes in EEG Measures Reflecting Functional Network Disruption in ALS Cognitive Phenotypes

Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:\ heta\\:$$\\end{document}-band spectral power over time in the temporal region along with increased \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:{\\gamma\\:}_{l}$$\\end{document}-band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS.

Different patterns of structural network impairments in two amyotrophic lateral sclerosis subtypes driven by 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging.

The structural network damages in amyotrophic lateral sclerosis patients are evident but contradictory due to the high heterogeneity of the disease. We hypothesized that patterns of structural network impairments would be different in amyotrophic lateral sclerosis subtypes by a data-driven method using 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid imaging. The data of positron emission tomography, structural MRI and diffusion tensor imaging in fifty patients with amyotrophic lateral sclerosis and 23 healthy controls were collected by a 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance hybrid. Two amyotrophic lateral sclerosis subtypes were identified as the optimal cluster based on grey matter volume and standardized uptake value ratio. Network metrics at the global, local and connection levels were compared to explore the impaired patterns of structural networks in the identified subtypes. Compared with healthy controls, the two amyotrophic lateral sclerosis subtypes displayed a pattern of a locally impaired structural network centralized in the sensorimotor network and a pattern of an extensively impaired structural network in the whole brain. When comparing the two amyotrophic lateral sclerosis subgroups by a support vector machine classifier based on the decreases in nodal efficiency of structural network, the individualized network scores were obtained in every amyotrophic lateral sclerosis patient and demonstrated a positive correlation with disease severity. We clustered two amyotrophic lateral sclerosis subtypes by a data-driven method, which encompassed different patterns of structural network impairments. Our results imply that amyotrophic lateral sclerosis may possess the intrinsic damaged pattern of white matter network and thus provide a latent direction for stratification in clinical research.

Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability

BackgroundUsing in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients.MethodsIn this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup.ResultsWe found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients.ConclusionOur study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.

Differing patterns of cortical grey matter pathology identified by multifractal analysis in UMN-predominant ALS patients with and without corticospinal tract hyperintensity

The pathological hallmarks of amyotrophic lateral sclerosis (ALS) are degeneration of the primary motor cortex grey matter (GM) and corticospinal tract (CST) resulting in upper motor neuron (UMN) dysfunction. Conventional brain magnetic resonance imaging (MRI) shows abnormal CST hyperintensity in some UMN-predominant ALS patients (ALS-CST+) but not in others (ALS-CST–). In addition to the CST differences, we aimed to determine whether GM degeneration differs between ALS-CST+ and ALS-CST– patients by cortical thickness (CT), voxel-based morphometry (VBM) and fractal dimension analyses. We hypothesized that MRI multifractal (MF) measures could differentiate between neurologic controls (n = 14) and UMN-predominant ALS patients as well as between patient subgroups (ALS-CST+, n = 21 vs ALS-CST–, n = 27). No significant differences were observed in CT or GM VBM in any brain regions between patients and controls or between ALS subgroups. MF analyses were performed separately on GM of the whole brain, of frontal, parietal, occipital, and temporal lobes as well as of cerebellum. Estimating MF measures D (Q = 0), D (Q = 1), D (Q = 2), Δf, Δα of frontal lobe GM classified neurologic controls, ALS-CST+ and ALS-CST– groups with 98% accuracy and > 95% in F1, recall, precision and specificity scores. Classification accuracy was only 74% when using whole brain MF measures and < 70% for other brain lobes. We demonstrate that MF analysis can distinguish UMN-predominant ALS subgroups based on GM changes, which the more commonly used quantitative approaches of CT and VBM cannot.

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an...

Brain metabolic signatures in patients with genetic and nongenetic amyotrophic lateral sclerosis.

To study the brain metabolic signature in Chinese amyotrophic lateral sclerosis (ALS) patients and compare the difference in brain metabolic patterns between ALS with and without genetic variants. We included 146 patients with ALS and 128 healthy controls (HCs). All patients with ALS underwent genetic testing to screen for ALS related genetic variants and were then divided into genetic (n = 22) and nongenetic ALS (n = 93) subgroups. All participants underwent brain 18 F-FDG-PET scans. Group comparisons were performed using the two-sample t-test model of SPM12. We identified a large of hypometabolic clusters in ALS patients as compared with HCs, especially in the bilateral basal ganglia, midbrain, and cerebellum. Moreover, hypometabolism in the bilateral temporal lobe, precentral gyrus and hypermetabolism in the left anterior cingulate, occipital lobe, and bilateral frontal lobe were also found in ALS patients as compared with HCs. Compared with nongenetic ALS patients, genetic ALS patients showed hypometabolism in the right postcentral gyrus, precuneus, and middle occipital gyrus. The incidence of sensory disturbance in patients with genetic ALS was higher than that in patients with nongenetic ALS (5 of 22 [22.72%] vs. 7 of 93 [7.52%], p = 0.036). Our investigation provided unprecedented evidence of relative hypometabolism in the midbrain and cerebellum in ALS patients. Genetic ALS patients showed a specific signature of brain metabolism and a higher incidence of sensory disturbance, indicating that genetic factors may be an underlying cause affecting the brain metabolism and increasing the risk of sensory disturbance in ALS.

The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

ObjectiveTo explore whether the repeat lengths of the chromosome 9 open reading frame 72 (C9orf72) gene and the ataxin-2 (ATXN2) gene in amyotrophic lateral sclerosis (ALS) patients without C9orf72 repeat expansions confer a risk of ALS or survival disadvantages in ALS.MethodsWe screened a hospital-based cohort of Chinese patients with sporadic ALS without C9orf72 repeat expansions and neurologically healthy controls for C9orf72 GGGGCC and AXTN2 CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum C9orf72 and ATXN2 repeat alleles, such as sex, age of onset, diagnostic delay, and survival.ResultsOverall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the C9orf72 and ATXN2 were both detected. We found significant survival differences in patients using a series of C9orf72 repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. >2: median survival 67 vs. 55 months, log-rank p = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03–1.05, p < 0.001], diagnostic delay (0.95, 0.94–0.96, p < 0.001), and carrying C9orf72 repeat length of 2 (0.72, 0.59–0.89, p = 0.002) in the survival of patients without C9orf72 repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum C9orf72 repeat allele over 2 (1.81, 1.32–2.48, p < 0.001). However, no survival difference was found when applying a series of continuous cutoff values of ATXN2 or stratified by C9orf72 repeats of 2.ConclusionThe length of 2 in the maximum C9orf72 repeat allele was identified to be associated with favorable survival in ALS patients without C9orf72 repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.

Detection of changes in synaptic density in amyotrophic lateral sclerosis patients using 18 F-SynVesT-1 positron emission tomography.

Synaptic loss is well established as the major correlate of characteristic and consistent pathology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of 18 F-SynVesT-1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes. Twenty-one patients with ALS and 25 healthy controls (HCs) were recruited. All participants underwent 18 F-SynVesT-1-PET. Synaptic density between ALS and HCs and between different ALS subgroups were compared. Correlation between synaptic density and clinical features in ALS was also analyzed. Low uptake distribution was found in the group comprising 21 ALS patients as compared with HCs in the right temporal lobe and the bilateral inferior frontal gyrus, anterior cingulate, and hippocampus-insula region. We also found low uptake in the bilateral superior temporal gyrus, hippocampus-insula, anterior cingulate, and left inferior frontal gyrus in ALS patients with cognitive impairment compared to HCs. Furthermore, compared to spinal onset ALS, bulbar onset ALS showed low uptake in the bilateral cingulate gyrus and high uptake in the bilateral superior temporal gyrus and left occipital lobe. No significant result was found in correlation analysis. This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS. 18 F-SynVesT-1-PET is presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS.

Alterations of Microstructure and Sodium Homeostasis in Fast Amyotrophic Lateral Sclerosis Progressors: A Brain DTI and Sodium MRI Study.

While conventional MR imaging has limited value in amyotrophic lateral sclerosis, nonconventional MR imaging has shown alterations of microstructure using diffusion MR imaging and recently sodium homeostasis with sodium MR imaging. We aimed to investigate the topography of brain regions showing combined microstructural and sodium homeostasis alterations in amyotrophic lateral sclerosis subgroups according to their disease-progression rates. Twenty-nine patients with amyotrophic lateral sclerosis and 24 age-matched healthy controls were recruited. Clinical assessments included disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Patients were clinically differentiated into fast (n = 13) and slow (n = 16) progressors according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale progression rate. 3T MR imaging brain protocol included 1H T1-weighted and diffusion sequences and a 23Na density-adapted radial sequence. Quantitative maps of diffusion with fractional anisotropy, mean diffusivity, and total sodium concentration were measured. The topography of diffusion and sodium abnormalities was assessed by voxelwise analyses. Patients with amyotrophic lateral sclerosis showed significantly higher sodium concentrations and lower fractional anisotropy, along with higher sodium concentrations and higher mean diffusivity compared with healthy controls, primarily within the corticospinal tracts, corona radiata, and body and genu of the corpus callosum. Fast progressors showed wider-spread abnormalities mainly in the frontal areas. In slow progressors, only fractional anisotropy measures showed abnormalities compared with healthy controls, localized in focal regions of the corticospinal tracts, the body of corpus callosum, corona radiata, and thalamic radiation. The present study evidenced widespread combined microstructural and sodium homeostasis brain alterations in fast amyotrophic lateral sclerosis progressors.

Repeated neurofilament light chain measurements did not capture Riluzole therapeutic effect in amyotrophic lateral sclerosis patients.

BackgroundLittle is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial.MethodsSera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single‐molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis.ResultssNfL levels were higher in ALS patients than in controls at the two time points (p < 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p < 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p < 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale‐revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p < 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003).ConclusionsIn this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.

Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.

Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.

P 76 MUNIX in combination with D50 disease progression model reflects disease accumulation independently of disease aggressiveness in Amyotrophic Lateral Sclerosis

Introduction: Motor Unit Number Index (MUNIX) is a reliable and non-invasive neurophysiological technique to reflect functional loss of motor units in amyotrophic lateral sclerosis (ALS). MUNIX is even able to show loss of motor units in pre-symptomatic, non-wasted muscles [1,2]. So, it has been recognized as a promising biomarker in ALS. ALS, as a multisystemic neurodegenerative disease, shows a high heterogeneity in clinical presentation, including disease phenotypes, progression and survival. We urgently need reliable surrogate markers to describe the individual disease course, reduce diagnostic delay and monitor efficacy of therapeutic strategies in ALS [3]. Additionally to MUNIX, we use the D50 disease progression model to analyze disease aggressiveness and disease accumulation. Patients and Methods: 237 ALS patients, 45 healthy controls and 22 ALS-Mimics received MUNIX of abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) in clinical routine by trained and certified electrophysiologists using a standardized protocol [4]. MUNIX was further analyzed by disease aggressiveness (D50) and disease accumulation (rD50 phase) in ALS using the D50 progression model. Results: MUNIX and CMAP were significantly lower in ALS patients and ALS-mimics compared to healthy controls (p < 0,05) in all investigated muscles. In ALS subgroup analysis, MUNIX in APB and TA showed significant decrease between rD50 Phase I and II (p < 0,001/p < 0,01), while significant differences in ADM just occurred in advanced disease stage between Phase II and III/IV (p < 0,05). Throughout the subgroups of aggressiveness, there were no significant differences. Conclusion: MUNIX in combination with D50 progression model demonstrates disease accumulation in ALS, especially in APB in early disease compared to ADM. This supports the clinical split-hand-phenomenon. Also, MUNIX seems to be independent of disease aggressiveness. Therefore, we apply MUNIX in combination with the D50 disease progression model to reflect the individual disease course in ALS, which might be useful in clinical trials to evaluate therapeutic strategies and agents in ALS independently of disease aggressiveness.

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.

Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics

Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.

Corticospinal Tract and Related Grey Matter Morphometric Shape Analysis in ALS Phenotypes: A Fractal Dimension Study

A pathological hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract (CST) degeneration resulting in upper motor neuron (UMN) dysfunction. No quantitative test is available to easily assess UMN pathways. Brain neuroimaging in ALS promises to potentially change this through identifying biomarkers of UMN dysfunction that may accelerate diagnosis and track disease progression. Fractal dimension (FD) has successfully been used to quantify brain grey matter (GM) and white matter (WM) shape complexity in various neurological disorders. Therefore, we investigated CST and whole brain GM and WM morphometric changes using FD analyses in ALS patients with different phenotypes. We hypothesized that FD would detect differences between ALS patients and neurologic controls and even between the ALS subgroups. Neuroimaging was performed in neurologic controls (n = 14), and ALS patients (n = 75). ALS patients were assigned into four groups based on their clinical or radiographic phenotypes. FD values were estimated for brain WM and GM structures. Patients with ALS and frontotemporal dementia (ALS-FTD) showed significantly higher CST FD values and lower primary motor and sensory cortex GM FD values compared to other ALS groups. No other group of ALS patients revealed significant FD value changes when compared to neurologic controls or with other ALS patient groups. These findings support a more severe disease process in ALS-FTD patients compared to other ALS patient groups. FD value measures may be a sensitive index to evaluate GM and WM (including CST) degeneration in ALS patients.

Disease aggressiveness signatures of amyotrophic lateral sclerosis in white matter tracts revealed by the D50 disease progression model.

Numerous neuroimaging studies in amyotrophic lateral sclerosis (ALS) have reported links between structural changes and clinical data; however phenotypic and disease course heterogeneity have occluded robust associations. The present study used the novel D50 model, which distinguishes between disease accumulation and aggressiveness, to probe correlations with measures of diffusion tensor imaging (DTI). DTI scans of 145 ALS patients and 69 controls were analyzed using tract‐based‐spatial‐statistics of fractional anisotropy (FA), mean‐ (MD), radial (RD), and axial diffusivity (AD) maps. Intergroup contrasts were calculated between patients and controls, and between ALS subgroups: based on (a) the individual disease covered (Phase I vs. II) or b) patients' disease aggressiveness (D50 value). Regression analyses were used to probe correlations with model‐derived parameters. Case–control comparisons revealed widespread ALS‐related white matter pathology with decreased FA and increased MD/RD. These affected pathways showed also correlations with the accumulated disease for increased MD/RD, driven by the subgroup of Phase I patients. No significant differences were noted between patients in Phase I and II for any of the contrasts. Patients with high disease aggressiveness (D50 < 30 months) displayed increased AD/MD in bifrontal and biparietal pathways, which was corroborated by significant voxel‐wise regressions with D50. Application of the D50 model revealed associations between DTI measures and ALS pathology in Phase I, representing individual disease accumulation early in disease. Patients' overall disease aggressiveness correlated robustly with the extent of DTI changes. We recommend the D50 model for studies developing/validating neuroimaging or other biomarkers for ALS.

Study on sleep-wake disorders in patients with genetic and non-genetic amyotrophic lateral sclerosis

ObjectiveTo study the frequency and clinical features of sleep disturbances in amyotrophic lateral sclerosis (ALS) patients and compare sleep disorders between ALS with and without mutations.MethodsIn this case–control study, 204...

A susceptibility-weighted imaging qualitative score of the motor cortex may be a useful tool for distinguishing clinical phenotypes in amyotrophic lateral sclerosis.

To distinguish amyotrophic lateral sclerosis (ALS) and its subtypes from ALS mimics and healthy controls based on the assessment of iron-related hypointensity of the primary motor cortex in susceptibility-weighted imaging (SWI). We enrolled 64 patients who had undergone magnetic resonance imaging studies with clinical suspicions of ALS. The ALS group included 48 patients; the ALS-mimicking disorder group had 16 patients. The ALS group was divided into three subgroups according to the prevalence of upper motor neuron (UMN) or lower motor neuron (LMN) impairment, with 12 subjects in the UMN-predominant ALS group (UMN-ALS), 16 in the LMN-predominant ALS group (LMN-ALS), and 20 with no prevalent impairment (C-ALS). The Motor Cortex Susceptibility (MCS) score was defined according to the hypointensity of the primary motor cortex in the SWI sequence. Its diagnostic accuracy in differentiating groups was evaluated. The MCS was higher in the ALS group than in the healthy control and ALS-mimicking disorder groups (p< 0.001). Among ALS subgroups, the MCS was significantly higher in the UMN-ALS group than in the healthy control (p< 0.001), ALS-mimicking disorder (p= 0.002), and LMN-ALS groups (p= 0.002) and higher in the C-ALS group than in the healthy control group (p= 0.019). An MCS value ≥ 2 showed specificity and a positive predictive value of 100% in the detection of both UMN-ALS and C-ALS patients. The assessment of MCS in the SWI sequence could be a useful tool in supporting diagnosis in patients suspicious for ALS with prevalent signs of UMN impairment or with no prevalence signs of UMN or LMN impairment. • The hypointensity of the primary motor cortex in susceptibility-weighted imaging could support the diagnosis of ALS. • Our new qualitative score called MCS shows high specificity and positive predictive value in differentiating ALS patients with upper motor neuron impairment from patients with ALS-mimicking disorders and healthy controls.

MRI study of paraspinal muscles in patients with Amyotrophic Lateral Sclerosis (ALS).

Background: the study of paraspinal muscles is pivotal for the diagnosis and staging of Amyotrophic Lateral Sclerosis (ALS), and is usually performed by electromyography. Objective: to evaluate the role of paraspinal muscle MRI as a diagnostic biomarker in ALS. Methods: we evaluated T1-w images of newly diagnosed ALS patients (n = 14), age-matched healthy controls (n = 11), patients affected by inflammatory myopathy (n = 10), and lumbar radiculopathy (n = 19), and compared them semiquantitatively by using the Mercuri Scale. Results: a significant difference in the appearance of the psoas muscle was observed between ALS patients and patients with radiculopathy (p = 0.003); after stratifying ALS patients into spinal and bulbar onsets, we found a significant difference in the appearance of the longissimus dorsi muscle between the spinal onset ALS subgroup and bulbar onset ALS subgroup (p = 0.0245), while no difference was found for multifidus (p = 0.1441), iliocostal (p = 0.0655), and psoas muscles (p = 0.0813) between the cohort subgroups. Conclusions: paraspinal T1-w MRI could help to distinguish spinal ALS patients from healthy and pathological controls. Specifically, the study of longissimus dorsi could play the role of a diagnostic ALS biomarker.

Patterns of brain regional functional coherence in cognitive impaired ALS

Background: The aim of the study is to reveal the brain regional functional coherence alterations in the early-stage amyotrophic lateral sclerosis (ALS) patients with cognitive impairments.Methods: Resting state functional MRI (fMRI) was performed to characterize the amplitude of regional homogeneity (ReHo). Twenty-one ALS patients with cognitive impairments (ALSci), 21 ALS patients without cognitive impairments (ALSnci) and 21 healthy controls (HCs) were enrolled.Result: Compared with HCs, the ALSci subgroup showed increased ReHo in bilateral inferior parietal lobules (IPLs), precuneus and inferior cerebellar areas, and the ALSnci subgroup had increased ReHo in the left IPL and left inferior cerebellar area. The ALSci subgroup also had increased ReHo in the right IPL and right inferior cerebellar area relative to the ALSnci subgroup. Meantime, compared with HCs, both ALS subgroups showed decreased ReHo in bilateral sensorimotor cortices. The ReHo values in the right cerebellar area were negatively correlated with the Chinese version of Addenbrooke Cognitive Examination–revised (ACE-R) total scores in all ALS patients. In addition, the grey matter (GM) volume revealed no significant difference among three groups, which indicated that the altered ReHo was not caused by the anatomic change.Conclusion: The altered regional functional coherence might indicate the underlying deficits of ALS with and without cognitive impairments. Our findings support that ALS is a multisystem disease and provide the evidence that alterations of ReHo in the right inferior cerebellar area might be a special marker of ALS with cognitive impairment. Our results are preliminary and further investigations are needed.