Amyotrophic Lateral Sclerosis Functional Rating Scale Research Articles

Quantitative ultrasound of the tongue: Echo intensity is a potential biomarker of bulbar dysfunction in amyotrophic lateral sclerosis

ObjectivesTo learn if quantitative ultrasound (QUS) distinguishes the tongues of healthy participants and amyotrophic lateral sclerosis (ALS) patients by echo intensity (EI) and to evaluate if EI correlates with measures of bulbar function. MethodsUltrasound was performed along the midline of the anterior tongue surface in 16 ALS patients and 16 age-matched controls using a linear hockey stick 16–7 MHz transducer. A region of interest was manually drawn and then EI was determined for the upper 1/3 of the muscle. For patients, the ALS functional rating scale – revised (ALSFRS-R) was used to calculate bulbar sub-scores and the Iowa Oral Performance Instrument (IOPI) was used to measure tongue strength. ResultsEI was significantly higher in ALS patients than in healthy participants (49.8 versus 37.8 arbitrary units, p < 0.01). In the patient group, EI was negatively correlated with ALSFRS-R bulbar sub-score (RS = −0.65, p < 0.01). An inverse correlation between EI and tongue strength did not reach significance (RS = −0.34, p = 0.28). ConclusionsThis study suggests that EI can differentiate healthy from diseased tongue muscle, and correlates with a standard functional measure in ALS patients. SignificanceTongue EI may represent a novel biomarker for bulbar dysfunction in ALS.

Longitudinal evaluation of upper motor neuron burden scales in primary lateral sclerosis

Objective To assess whether published scales for measuring upper motor neuron burden (UMNB) show longitudinal change in patients with primary lateral sclerosis (PLS). Design: Retrospective calculation of three UMNB scales on a prospectively collected dataset from 53 patients with PLS enrolled in a longitudinal natural history study with at least 2 evaluation visits. UMNB scales were calculated according to their published descriptions. Non-linear trends over time of UMNB scale scores and slopes were calculated for each patient and correlations between UMNB scores and clinical measures were assessed. Results: All three UMNB scales exhibited increasing scores over the first 7.8 years of symptoms, with a flattening in slope after approximately 8 years. A scale used in imaging studies and the UPENN UMNS scale provided a better fit to the dataset than the MGH UMNB scale. All three UMNB scales exhibited moderate correlations with some clinical measures of movement, such as finger-tapping rate and timed gait. Correlations were strongest for the UPENN UMNS, which was also moderately correlated with the revised ALS functional rating scale. Conclusion: In a cohort of PLS patients enrolled in a natural history study, the three UMNB scales exhibited modest linear increases over the first 8 years of symptoms, followed by a plateau. Future clinical trials in PLS should consider stratification of patients by disease duration. UMNB scales may be useful secondary outcomes, but more sensitive primary outcome measures are needed for clinical trials for PLS.

A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS.

To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. NCT02405182.

Peptide variability and signatures associated with disease progression in CSF collected longitudinally from ALS patients.

We employ shotgun proteomics and data-independent acquisition (DIA) mass spectrometry to analyze cerebrospinal fluid longitudinally collected from 14 amyotrophic lateral sclerosis (ALS) patients (8 males and 6 females). We perform three main analyses of these data: (1) examine the intra- and inter-patient protein variability in CSF; (2) explore the association of inflammation with rate of disease progression; and (3) develop a mixed-effects model to best explain the decrease in ALS-Functional Rating Scale (ALS-FRS) score. Overall, the CSF protein abundances are tightly regulated with the intra-individual variability contributing just 4% to the overall variance. In four patients, a moderately significant correlation (p < 0.1) was observed between inflammation and rate of disease progression. Using a least absolute shrinkage and selection operator (LASSO) variable selection, we selected 55 viable peptides for mathematical modeling via a linear mixed-effects regression. We then employed forward selection to generate a final model by minimizing Akaike's information criterion (AIC). The final model utilized changes in abundance from 28 peptides as fixed effects to model progression of the disease in these patients. These peptides were from proteins involved in stress response and innate immunity. Graphical abstract.

Correlations Between Median Nerve Sonography and Conduction Study Results and Functional Scales in Amyotrophic Lateral Sclerosis

We aimed to compare the sonographic measurement of median nerve cross-section area (CSA) in patients with Amyotrophic Lateral Sclerosis (ALS) and healthy individuals. The effect of duration of the disease on correlations between paraclinical findings and ALS functional rating scale (ALSFRS) were secondarily aimed to be evaluated. The cross-sectional study was approved by the Ethical Committee of Iran University of Medical Sciences and conducted between January 2017 and December 2018. We evaluated the median nerve surface area by means of sonography in 35 ALS patients and 35 healthy controls. Compound muscle action potential (CMAP) amplitudes during nerve conduction study and ALSFRS were recorded by the same trained specialist. Data were analyzed using SPSS software version 18. We did not find a significant difference between CSA in ALS patients and the normal population (P&gt;0.05). Comparing to normal individuals, the mean CMAP decreased significantly in ALS patients (6.6±3.07 mV versus 10.25±2.2 mV, P&lt;0.001). ALSFRS correlated with both CSA of the median nerve at the wrist (P:&lt;0.001, r:0.78) and the CMAP (P:&lt;0.001, r:0.74) that were confirmed by regression models designed to consider the effect of disease duration on these correlations. CSA was not different between ALS patients and the normal population, but CMAP decreased in ALS patients. ALSFRS correlated with both CSA and CMAP of the median nerve.

Improved ALS clinical trials through frequent at-home self-assessment: a proof of concept study.

ObjectiveTo determine the potential for improving amyotrophic lateral sclerosis (ALS) clinical trials by having patients or caregivers perform frequent self‐assessments at home.Methods and ParticipantsWe enrolled ALS patients into a nonblinded, longitudinal 9‐month study in which patients and caregivers obtained daily data using several different instruments, including a slow‐vital capacity device, a hand grip dynamometer, an electrical impedance myography‐based fitness device, an activity tracker, a speech app, and the ALS functional rating scale‐revised. Questions as to acceptability were asked at two time points.ResultsA total of 113 individuals enrolled, with 61 (43 men, 18 women, mean age 60.1 ± 9.9 years) collecting a minimum of 7 days data and being included in the analysis. Daily measurements resulted in more accurate assessments of the slope of progression of the disease, resulting in smaller sample size estimates for a hypothetical clinical trial. For example, by performing daily slow‐vital capacity measurements, calculated sample size was reduced to 182 subjects/study arm from 882/arm for monthly measurements. Similarly, performing the ALS functional rating scale weekly rather than monthly led to a calculated sample size of 73/arm as compared to 274/arm. Participants generally found the procedures acceptable and, for many, improved their sense of control of their disease.InterpretationFrequent at‐home measurements using standard tools holds the prospect of tracking progression and reducing sample size requirements for clinical trials in ALS while also being acceptable to the patients. Future studies in this and other neurological disorders should consider adopting this approach to data collection.

Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS.

To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

A nerve conduction study predicts the prognosis of sporadic amyotrophic lateral sclerosis.

To clarify the relationship between nerve conduction study (NCS) and prognosis in patients with amyotrophic lateral sclerosis (ALS). We included 190 patients with sporadic ALS. We used onset age, sex, onset site (bulbar vs. spinal), revised El Escorial criteria category (definite vs. others), and the King's clinical systems, and the Milano-Torino (MiToS) functional staging systems, and decline rates of revised ALS functional rating scale (ALSFRS-R) as known prognostic factors. An NCS was performed on the median, ulnar, tibial, and sural nerves. The endpoint was death or the introduction of tracheostomy positive-pressure ventilation. Multivariate analysis for each NCS variable, known prognostic factors was performed using Cox stepwise proportional hazards analysis. Univariate analysis was performed for NCS variables that showed a significant association with prognosis in multivariate analysis. Survival was analyzed with a Kaplan-Meier curve and log-rank test. The Cox model identified the compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of the median nerve as prognostic factors. In the log-rank test, patients with higher median nerve CMAP amplitude had a significantly better prognosis than those with lower amplitude, regardless of age. And prognosis was better in the group with lower median nerve SNAP amplitude only in patients younger than the 25th percentile (~ 57years). CMAP and SNAP amplitudes of the median nerve are considered to be independent prognostic factors of sporadic ALS.

Botulinum toxin for the treatment of lower limb cramp pain in patients with Amyotrophic Lateral Sclerosis

Background:&#x0D; Muscle cramps and pain associated with them can be seen in patients with amyotrophic lateral sclerosis (ALS) and are known to reduce the quality of life. Pharmacological treatment may not benefit all patients in treating these cramps. We assess the efficacy of Onabotulinum toxin A (BTX-A) in the treatment of lower limb cramps in patients with ALS.&#x0D; Methods:&#x0D; This retrospective chart review included a total of ten patients with ALS who suffered from pain due to lower limb cramps and were managed with BTX-A. Data including patient demographics, visual analog pain scale at different intervals during follow up, ALS functional rating scale and site of onset of ALS symptoms were documented. The pain score at baseline (before administration), at 3 months follow up and at 6 months follow up were compared using Wilcoxon test to assess BTX-A’s efficacy.&#x0D; Results:&#x0D; A significant improvement in average pain score due to cramps from baseline to the 6-month interval with a change of 3.1±0.7 (p&lt;0.05,95%CI) was seen on the pain scale. No adverse events were noted during administration or post injections.&#x0D; Conclusion:&#x0D; Local BTX-A administration is an efficacious and safe procedure for improving pain associated with cramps in patients with ALS.

The increase in CSF total protein and immunoglobulins in Chinese patients with sporadic amyotrophic lateral sclerosis: A retrospective study

ObjectiveThe objective of this study was to evaluate total protein (TP) in the cerebrospinal fluid (CSF) and immunoglobulins in the serum and CSF in patients with sporadic amyotrophic lateral sclerosis (sALS). We also assessed the correlations of these variables with sALS progression and severity and estimated their roles in predicting prognosis. MethodsWe retrospectively collected data on CSF TP and immunoglobulins in the CSF and serum, including immunoglobulin G, immunoglobulin A and immunoglobulin M, from 326 sALS patients. The relationships between these variables and clinical features, including sex, age, disease duration, site of onset, respiratory function and survival time, were analysed by Wilcoxon's nonparametric tests. Kaplan–Meier and Cox proportional hazards models were used to explore whether levels of TP and immunoglobulins in the CSF were independently correlated with the survival time of patients with ALS. ResultsThe CSF TP was elevated in 55% of the patients. The median CSF TP was 417.7 (349.4–539.5) mg/L, and 6 patients (2%) had a CSF TP level greater than 1000 mg/L. The CSF TP levels were significantly higher in male patients than in female patients (p<.001). In females, the CSF TP had positive associations with onset age (rho =0.196, p = .021) and disease progression rate (DPR) (rho =0.230, p = .035) but negative associations with disease duration (rho = −0.204, p = .016) and revised ALS functional rating scale (ALSFRS-R) (rho = −0.288, p = .008). The ALSFRS-R scores of male patients were negatively correlated with the s-IgM levels (rho = −0.562, p = .005). Onset age was negatively associated with the s-IgM levels (rho = −0.534, p = .005) in females. Kaplan–Meier survival analyses showed that no correlations were found between survival time and the levels of TP and immunoglobulins in the CSF. ConclusionElevated levels of TP and immunoglobulins in the CSF suggest impaired blood-brain barrier (BBB) function and immune responses in the CNS of ALS patients. Higher CSF TP levels were associated with later onset age, a shorter disease duration and worse disease severity in females. The changes in the levels of CSF TP and s-IgM might indicate the severity of the disease in some ALS patients.

Identification of Amyotrophic Lateral Sclerosis Based on Diffusion Tensor Imaging and Support Vector Machine.

Objectives: White matter (WM) impairments involving both motor and extra-motor areas have been well-documented in amyotrophic lateral sclerosis (ALS). This study tested the potential of diffusion measurements in WM for identifying ALS based on support vector machine (SVM).Methods: Voxel-wise fractional anisotropy (FA) values of diffusion tensor images (DTI) were extracted from 22 ALS patients and 26 healthy controls and served as discrimination features. The revised ALS Functional Rating Scale (ALSFRS-R) was employed to assess ALS severity. Feature ranking and selection were based on Fisher scores. A linear kernel SVM algorithm was applied to build the classification model, from which the classification performance was evaluated. To promote classifier generalization ability, a leave-one-out cross-validation (LOOCV) method was adopted.Results: By using the 2,400~3,400 ranked features as optimal features, the highest classification accuracy of 83.33% (sensitivity = 77.27% and specificity = 88.46%, P = 0.0001) was achieved, with an area under receiver operating characteristic curve of 0.862. The predicted function value was positively correlated with patient ALSFRS-R scores (r = 0.493, P = 0.020). In the optimized SVM model, FA values from several regions mostly contributed to classification, primarily involving the corticospinal tract pathway, postcentral gyrus, and frontal and parietal areas.Conclusions: Our results suggest the feasibility of ALS diagnosis based on SVM analysis and diffusion measurements of WM. Additional investigations using a larger cohort is recommended in order to validate the results of this study.

Electrical impedance myography (EIM) in a natural history study of C9ORF72 mutation carriers

Objective: Electrical Impedance Myography (EIM) was used to evaluate disease progression in subjects with C9ORF72 expansion mutations and to assess correlations with Medical Research Council (MRC) Scale and revised ALS Functional Rating Scale (ALSFRS-R) measurements. Four types of clinical presentations were assessed; Amyotrophic Lateral Sclerosis (ALS), Frontotemporal dementia (FTD) or other dementia, ALS-FTD, and asymptomatic (ASYMP). Methods: Subjects were divided into an ALS Group (ALS/ALS-FTD) and non-ALS Group (FTD/ASYMP) based on initial visit and evaluated at 0, 6, 18, and 30 months with EIM of 4 arm and 4 leg muscles, ALSFRS-R, and MRC scales. The change in EIM from baseline and correlation with the functional scale and strength testing were analyzed. Results: EIM 50kHz phase values significantly declined over time in the ALS group (n = 31) compared to the non-ALS group (FTD/ASYMP) (n = 19). In the ALS group, the decline in EIM was correlated with decline in the ALSFRS-R and MRC scores using within-subject correlations. Conclusion: In clinical trials with small populations of genetically associated ALS such as C9ORF-related ALS, EIM may be a useful quantitative biomarker. We did not detect decline in asymptomatic subjects, but longer term studies may detect early changes in this group.

Cortical hyperexcitability evolves with disease progression in ALS.

ObjectiveCortical hyperexcitability has been established as an early feature of amyotrophic lateral sclerosis (ALS). The evolution of cortical hyperexcitability with ALS progression remains to be fully elucidated. This study aims to investigate changes in cortical function in ALS with disease progression.MethodsCortical function assessed by threshold tracking transcranial magnetic stimulation (TMS) along with clinical phenotyping was prospectively undertaken on 444 patients presenting with suspected ALS (345 ALS; 99 neuromuscular mimics). Disease stage was defined as follows: (1) King’s clinical staging system and (2) proportion of disease duration statistically categorized into tertials.ResultsCortical hyperexcitability was evident across all ALS stages, being more prominent in later stages of ALS as indicated by increased motor‐evoked potential amplitude (P < 0.05), as well as longer disease duration as reflected by reduced short‐interval intracortical inhibition (P < 0.05). Prolonged central motor conduction time was evident with disease progression. These changes were accompanied by reduction in neurophysiological index (P < 0.001) and compound muscle action potential amplitude (P < 0.01), progressive muscle weakness (P < 0.001), and decline in the ALS functional rating scale (P < 0.001).InterpretationThis study established an increase in cortical hyperexcitability with increased disease duration in ALS, mediated by cortical disinhibition and direct increase in corticomotoneuronal excitability.

Diaphragmatic CMAP amplitude from phrenic nerve stimulation predicts functional decline in ALS.

To evaluate phrenic nerve motor amplitude (PhrenicAmp) as an independent predictor of functional decline in amyotrophic lateral sclerosis (ALS). We also assessed both PhrenicAmp and forced vital capacity (FVC) as predictors of functional loss in patients with bulbar dysfunction. We included consecutive ALS patients with PhrenicAmp and FVC at baseline. Participants were evaluated with the revised ALS Functional Rating Scale (ALSFRS-R) at inclusion and at, at least, one subsequent follow-up visit. The outcome measure of functional decline was the percentage reduction in ALSFRS-R from baseline. Bulbar dysfunction was defined by the presence of any relevant symptom on the ALSFRS-R bulbar sub-score. Correlations and mixed-effects regressions were used to study the relationship between functional decline and both PhrenicAmp and FVC baseline evaluations. A total of 249 ALS patients were included; 64.2% of these had bulbar dysfunction. At inclusion, significant correlations were found between PhrenicAmp and FVC (p < 0.001), as well as between each respiratory measure and ALSFRS-R (all p < 0.001). The functional decline at first (median 3months) and second (median 6months) follow-up visits was significantly correlated with baseline values of both respiratory evaluations (all p < 0.01) in the entire ALS population, but only with baseline PhrenicAmp (all p < 0.05) in bulbar dysfunction cases. Regression analysis revealed that PhrenicAmp (all p < 0.05), but not FVC, was a significant independent predictor of functional decline in ALS patients and in those with bulbar dysfunction. Baseline PhrenicAmp is an independent predictor of functional decline in ALS, whether or not bulbar dysfunction is present.

Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis

Neuroinflammation is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), but only limited data are available on systematic peripheral and central immune cell profiles in ALS. We studied detailed immune profiles of 73 ALS patients and 48 healthy controls (controls) in peripheral blood by fluorescence-activated cell sorting as well as cytokine expression profiles in serum. In a subgroup of 16 ALS patients and 10 controls we additionally studied cerebrospinal fluid (CSF) samples. In peripheral blood, T cell subtypes presented a shift towards pro-inflammatory Th 1 and Th 17 cells whereas anti-inflammatory Th2 and T regulatory cells were decreased. Important players in innate immunity including distinct monocyte (Mo) and natural killer (NK) cell subtypes were changed in ALS patients compared to controls. Pro-inflammatory serum cytokines such as interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) were increased and the anti-inflammatory cytokine IL-10 was decreased. Correlation analysis revealed moderate negative correlations between Th1 and Th17 to the ALS functional rating scale revised (ALSFRS-R) and to forced vital capacity. In CSF samples, no relevant alteration of the immune profile was found. In conclusion, the immune profile in ALS was shifted towards a Th1/Th17 cell-mediated pro-inflammatory immune response and correlated to disease severity and progression. Large prospective studies are needed to confirm these findings.

Increased cerebrospinal fluid levels of cytokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in patients with amyotrophic lateral sclerosis

IntroductionNeuroinflammation has recently been described in amyotrophic lateral sclerosis (ALS). However, the precise role of such proinflammatory cytokines as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in ALS has not yet been determined. In this study, we determined cerebrospinal fluid (CSF) MCP-1 and MIP-1β levels and assessed their association with the duration and severity of ALS. MethodsConcentrations of MCP-1 and MIP-1β were determined in the CSF of 77 patients diagnosed with ALS and 13 controls. Cytokine levels were analysed in relation to ALS duration (< 12months vs > 12months) and severity (< 30points vs > 30points on the ALS Functional Rating Scale administered at hospital admission). ResultsHigher CSF MIP-1β (10.68pg/mL vs 4.69pg/mL, P<.0001) and MCP-1 (234.89pg/mL vs 160.95pg/mL, P=.011) levels were found in the 77 patients with ALS compared to controls. There were no differences in levels of either cytokine in relation to disease duration or severity. However, we did observe a significant positive correlation between MIP-1β and MCP-1 in patients with ALS. ConclusionsThe increase in MIP-1β and MCP-1 levels suggests that these cytokines may have a synergistic effect on ALS pathogenesis. However, in our cohort, no association was found with either the duration or the clinical severity of the disease.

Brain Cortical Complexity Alteration in Amyotrophic Lateral Sclerosis: A Preliminary Fractal Dimensionality Study.

Objective Fractal dimensionality (FD) analysis provides a quantitative description of brain structural complexity. The application of FD analysis has provided evidence of amyotrophic lateral sclerosis- (ALS-) related white matter degeneration. This study is aimed at evaluating, for the first time, FD alterations in a gray matter in ALS and determining its association with clinical parameters. Materials and Methods. This study included 22 patients diagnosed with ALS and 20 healthy subjects who underwent high-resolution T1-weighted imaging scanning. Disease severity was assessed using the revised ALS Functional Rating Scale (ALSFRS-R). The duration of symptoms and rate of disease progression were also assessed. The regional FD value was calculated by a computational anatomy toolbox and compared among groups. The relationship between cortical FD values and clinical parameters was evaluated by Spearman correlation analysis. Results ALS patients showed decreased FD values in the left precentral gyrus and central sulcus, left circular sulcus of insula (superior segment), left cingulate gyrus and sulcus (middle-posterior part), right precentral gyrus, and right postcentral gyrus. The FD values in the right precentral gyrus were positively correlated to ALSFRS-R scores (r = 0.44 and P = 0.023), whereas negatively correlated to the rate of disease progression (r = 0.44 and P = 0.023), whereas negatively correlated to the rate of disease progression (r = 0.44 and P = 0.023), whereas negatively correlated to the rate of disease progression (Conclusions Our results suggest an ALS-related reduction in structural complexity involving the gray matter. FD analysis may shed more light on the pathophysiology of ALS.

Dyspnea as a Fatigue-Promoting Factor in ALS and the Role of Objective Indicators of Respiratory Impairment

ContextThere is no evidence-based treatment for fatigue in amyotrophic lateral sclerosis (ALS), and identification of treatable causes determines management strategies. Although dyspnea is a key symptom of ALS and effectively treatable, it has not been sufficiently investigated whether dyspnea may be a fatigue-promoting factor. ObjectivesTo determine the level of fatigue in dyspneic ALS patients and whether fatigue is promoted by dyspnea. We further evaluated the correlation of fatigue with respiratory function tests. MethodsAbout 101 dyspneic patients and 20 matched controls completed the ALS Functional Rating Scale—Extension and the Fatigue Severity Scale. Dyspneic patients additionally completed the Dyspnea-ALS Scale and the ALS Assessment Questionnaire and underwent respiratory function tests (forced vital capacity, sniff nasal inspiratory pressure, mean inspiratory and expiratory pressure with respective relaxation rates, and blood gases). Multiple regression and correlation analyses were conducted. ResultsDyspneic patients had significantly higher fatigue scores than nondyspneic patients, and their fatigue significantly affected quality of life. Dyspnea alone explained up to 24% of the variance in fatigue. No associations were observed between fatigue and respiratory function tests. Patients with noninvasive ventilation reported significantly more dyspnea and fatigue. ConclusionFatigue is a frequent and bothersome symptom in dyspneic ALS patients. Dyspnea-related distress is, in contrast to objective indicators of respiratory impairment, a determining factor of experienced fatigue. There is an urgent need for further symptom relief beyond noninvasive ventilation. Adequate treatment of dyspnea has the potential for synergies in symptom management arising from the association between fatigue and dyspnea.

Local and Systemic Humoral Response to Autologous Lineage-Negative Cells Intrathecal Administration in ALS Patients.

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin−) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin− cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

The upper cervical spinal cord in ALS assessed by cross-sectional and longitudinal 3T MRI

The upper cervical spinal cord is measured in a large longitudinal amyotrophic lateral sclerosis (ALS) cohort to evaluate its role as a biomarker. Specifically, the cervical spinal cord´s cross-sectional area (CSA) in plane of the segments C1–C3 was measured semi-automatically with T1-weighted 3T MRI sequences in 158 ALS patients and 86 controls. Six-month longitudinal follow-up MRI scans were analyzed in 103 patients. Compared to controls, in ALS there was a significant mean spinal cord atrophy (63.8 mm² vs. 60.8 mm², p = 0.001) which showed a trend towards worsening over time (mean spinal cord CSA decrease from 61.4 mm² to 60.6 mm² after 6 months, p = 0.06). Findings were most pronounced in the caudal segments of the upper cervical spinal cord and in limb-onset ALS. Baseline CSA was related to the revised ALS functional rating scale, disease duration, precentral gyrus thickness and total brain gray matter volume. In conclusion, spinal cord atrophy as assessed in brain MRIs in ALS patients mirrors the extent of overall neurodegeneration and parallels disease severity.