Longitudinal Quantitative MRI Evaluation of Muscle Involvement in Amyotrophic Lateral Sclerosis

Background: Biomarkers of disease progression and outcome measures are still lacking for patients with amyotrophic lateral sclerosis (ALS). Muscle MRI can be a promising candidate to track longitudinal changes and to predict response to the therapy in clinical trials.Objective: Our aim is to apply quantitative muscle MRI in the evaluation of disease progression, focusing on thigh and leg muscles of patients with ALS, and to explore the correlation between radiological and clinical scores.Methods: We enrolled newly diagnosed patients with ALS, longitudinally scored using the ALS Functional Rating Scale-Revised (ALSFRS-R), who underwent a 3T muscle MRI protocol including a 6-point Dixon gradient-echo sequence and multi-echo turbo spin echo (TSE) T2-weighted sequence for quantification of fat fraction (FF), cross-sectional area (CSA), and water T2 (wT2). A total of 12 muscles of the thigh and six muscles of the leg were assessed by the manual drawing of 18 regions of interest (ROIs), for each side. A group of 11 age-matched healthy controls (HCs) was enrolled for comparison.Results: 15 patients (M/F 8/7; mean age 62.2 years old, range 29–79) diagnosed with possible (n = 2), probable (n = 12), or definite (n = 1) ALS were enrolled. Eleven patients presented spinal onset, whereas four of them had initial bulbar involvement. All patients performed MRI at T0, nine of them at T1, and seven of them at T2. At baseline, wT2 was significantly elevated in ALS subjects compared to HCs for several muscles of the thigh and mainly for leg muscles. By contrast, FF was elevated in few muscles, and mainly at the level of the thigh. The applied mixed effects model showed that FF increased significantly in the leg muscles over time (mainly in the triceps surae) and that wT2 decreased significantly in line with worsening in the leg subscore of ALSFRS-R, mainly at the leg level and in the anterior and medial compartment of the thigh.Conclusions: Quantitative MRI represents a non-invasive tool that is able to outline the trajectory of pathogenic modifications at the muscle level in ALS. In particular, wT2 was found to be increased early in the clinical history of ALS and also tended to decrease over time, also showing a positive correlation with leg subscore of ALSFRS-R.

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Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10081623 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1623

Author(s):

Maria Viktoria Requardt ◽

Dennis Görlich ◽

Torsten Grehl ◽

Matthias Boentert

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Disease Progression ◽

Rating Scale ◽

Rapid Decline ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Hazard Ratios ◽

Sum Score ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome.

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Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study

Neurological Sciences ◽

10.1007/s10072-021-05723-z ◽

2021 ◽

Author(s):

Mónica Povedano ◽

Andrés Paipa ◽

Miquel Barceló ◽

Michael K. Woodward ◽

Sandra Ortega ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pilot Study ◽

Disease Progression ◽

Plasma Exchange ◽

Rating Scale ◽

Open Label ◽

Primary Endpoints ◽

Rate Of Decline ◽

Post Hoc ◽

Lateral Sclerosis

Abstract Background Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer’s disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. Methods In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months’ treatment with PE-A 5% and 6 months’ follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. Results The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. Conclusion Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EudraCT number 2013-004842-40. Trial registration ClinicalTrials.gov identifier: NCT02479802.

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Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS)

BMJ Open ◽

10.1136/bmjopen-2018-028486 ◽

2019 ◽

Vol 9 (5) ◽

pp. e028486 ◽

Cited By ~ 11

Author(s):

Jessica Mandrioli ◽

Valeria Crippa ◽

Cristina Cereda ◽

Valentina Bonetto ◽

Elisabetta Zucchi ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Phase Ii ◽

Mononuclear Cells ◽

Rating Scale ◽

Double Blind ◽

Peripheral Blood Mononuclear ◽

Double Blind Placebo ◽

Lateral Sclerosis

IntroductionDisruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8–BAG3–HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.Methods and analysisColchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients’ association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.Trial registration numberEUDRACT 2017-004459-21;NCT03693781; Pre-results.

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Correlations in health status between estimates of families of people with amyotrophic lateral sclerosis and estimates of staff

Palliative & Supportive Care ◽

10.1017/s1478951512000089 ◽

2012 ◽

Vol 11 (3) ◽

pp. 183-189 ◽

Cited By ~ 1

Author(s):

Anneli G. Ozanne ◽

Lennart I. Persson

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Analogue Scale ◽

Rating Scale ◽

Well Being ◽

Life Situation ◽

Next Of Kin ◽

Holistic View ◽

The Family ◽

Lateral Sclerosis ◽

Over Time

AbstractObjective:The aim of this study was to compare self-estimates of the physical, psychological, and general well-being of patients with amyotrophic lateral sclerosis (ALS) and their next of kin with the assessment of the nurses and physician of these participants.Method:The well-being of 35 pairs of patients and their next of kin was rated by themselves, and by a physician and nurses. The well-being was examined over time, using a visual analogue scale (VAS). Patients' physical function was estimated at the same time with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and the Norris scale.Results:The correlations between the staff's estimates of the well-being of patients and next of kin were similar to their own estimates, even though staff to a higher degree estimated a decrease in well-being over time among the patients. The estimates by the nurses correlated better to that of the patients and next of kin in psychological and general well-being than the physicians' estimates did.Significance of results:Even though the staff's estimates of participants were roughly equivalent to their self-estimates, there were some differences. This result calls attention to the importance of working in teams in which different professional roles are combined and integrated, making it possible to form a holistic view of the situation of each family. A concern overlooked by one member of staff might be covered by another, and different focuses on the family may give a better composite picture of their life situation, which could lead to better support to the family.

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TDP-43–specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000937 ◽

2020 ◽

Vol 8 (2) ◽

pp. e937

Author(s):

Anne Kallehauge Nielsen ◽

Jonas Folke ◽

Sylwia Owczarek ◽

Kirsten Svenstrup ◽

Kristian Winge ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Disease Duration ◽

Rating Scale ◽

High Avidity ◽

Naturally Occurring ◽

Specific Autoantibody ◽

Normal Controls ◽

Lateral Sclerosis ◽

Isotype Igg1

ObjectiveWe hypothesize alterations in the quality and quantity of anti–43-kDa TAR DNA-binding protein (TDP-43) naturally occurring autoantibodies (NAbs) in patients with amyotrophic lateral sclerosis (ALS); therefore, we assessed relative binding properties of anti–TDP-43 NAbs composite in plasma from patients with ALS in comparison with healthy individuals.MethodsELISA competition assay was used to explore the apparent avidity/affinity of anti–TDP-43 NAbs in plasma from 51 normal controls and 30 patients with ALS. Furthermore, the relative levels of anti–TDP-43 NAbs within the immunoglobulin (Ig) classes of IgG (isotype IgG1-4) and IgMs were measured using classical indirect ELISA. The occurring results were hereafter correlated with the measures of disease duration and disease progression.ResultsHigh-avidity/affinity anti–TDP-43 NAbs levels were significantly reduced in plasma samples from patients with ALS. In addition, a significant decrease in relative levels of anti–TDP-43 IgG3 and IgM NAbs and a significant increase in anti–TDP-43 IgG4 NAbs were observed in ALS plasma vs controls. Furthermore, a decrease in global IgM and an increase in IgG4 levels were observed in ALS. These aberrations of humoral immunity correlated with disease duration, but did not correlate with ALS Functional Rating Scale–Revised scores.ConclusionsOur results may suggest TDP-43–specific immune aberrations in patients with ALS. The skewed immune profiles observed in patients with ALS could indicate a deficiency in the clearance capacity and/or blocking of TDP-43 transmission and propagation. The decrease in levels of high affinity/avidity anti-TDP-43 NAbs and IgMs correlates with disease progression and may be disease predictors.

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Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial

BMJ Open ◽

10.1136/bmjopen-2019-029449 ◽

2019 ◽

Vol 9 (11) ◽

pp. e029449 ◽

Cited By ~ 4

Author(s):

Berzenn Urbi ◽

Simon Broadley ◽

Richard Bedlack ◽

Ethan Russo ◽

Arman Sabet

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Rating Scale ◽

Numeric Rating Scale ◽

Motor Neurone ◽

Double Blind ◽

Based Medicine ◽

Numeric Rating ◽

Lateral Sclerosis

IntroductionAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3–5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.Methods and analysisThe Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire.Ethics and disseminationThe study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal.Trial registration numberNCT03690791

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

BioMed Research International ◽

10.1155/2020/1521679 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Jian-Hua Chen ◽

Nao-Xin Huang ◽

Tian-Xiu Zou ◽

Hua-Jun Chen

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Gray Matter ◽

Rating Scale ◽

Structural Complexity ◽

Fractal Dimensionality ◽

Clinical Parameters ◽

Precentral Gyrus ◽

Duration Of Symptoms ◽

Lateral Sclerosis

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=−0.41 and P=0.039). Meanwhile, the FD value in the left circular sulcus of the insula (superior segment) was negatively correlated to disease duration (r=−0.51 and P=0.010). 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.

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Serum asymmetric dimethyl arginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

10.1101/2021.07.01.21259228 ◽

2021 ◽

Author(s):

Kensuke Ikenaka ◽

Yasuhiro Maeda ◽

Hotta Yuji ◽

Seiichi Nagano ◽

Keita Kakuda ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Rating Scale ◽

Proportional Hazards Model ◽

Cox Proportional Hazards Model ◽

No Production ◽

Adma Level ◽

Neurofilament Light Chain ◽

Sporadic Als ◽

Lateral Sclerosis

Objective: To investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS. Methods: Serum ADMA levels of patients with sporadic ALS (n = 68) and disease control patients (n = 54) were measured using liquid chromatography tandem mass spectrometry. Serum samples were obtained at the time of patient registration for diagnosis. Correlations of ADMA level and other markers (nitric oxide (NO) and neurofilament light chain (NFL) levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRSR) score from the onset of disease (ALSFRSR preslope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan Meier analysis. Results: The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001), and was independently associated with the ALSFRSR preslope (r = 0.505. p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF NfL level (r = 0.456, p = 0.0002) but not with NO level (r = 0.194, p = 0.219). Conclusion: ADMA level is an independent biomarker of ALS disease progression and prognosis, and reflects the degree of motor neuron degeneration. The increased ADMA level in ALS patients was not associated with the inhibition of NO production.

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Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials

Translational Neurodegeneration ◽

10.1186/s40035-021-00257-y ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Simon Witzel ◽

Felix Frauhammer ◽

Petra Steinacker ◽

David Devos ◽

Pierre-François Pradat ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Observational Study ◽

Prediction Model ◽

Disease Progression ◽

Statistical Power ◽

Rating Scale ◽

Disease Onset ◽

Neurofilament Light ◽

The Impact ◽

Lateral Sclerosis

Abstract Background Interventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power. Methods In 125 patients with ALS from three independent prospective studies—one observational study and two interventional trials—we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS). Results Among the parameters provided, the NfL levels (P < 0.001) and the interaction with site of onset (P < 0.01) contributed significantly to the prediction, forming a robust NfL prediction model (R = 0.67). Model application in the trial cohorts confirmed its applicability and revealed superiority over lead-in and ΔFRS-based approaches. The NfL model improved statistical power by 61% and 22% (95% confidence intervals: 54%–66%, 7%–29%). Conclusion The use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could significantly increase the trial power. NCT00868166, registered March 23, 2009; NCT02306590, registered December 2, 2014.

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How COVID-19 pandemic changed our management strategies for amyotrophic lateral sclerosis (ALS) patients: Egyptian study

The Egyptian Journal of Neurology Psychiatry and Neurosurgery ◽

10.1186/s41983-021-00331-2 ◽

2021 ◽

Vol 57 (1) ◽

Author(s):

Hebatallah R. Rashed

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

North Africa ◽

Rating Scale ◽

Management Strategies ◽

Office Visits ◽

Bulbar Onset ◽

A Prospective Study ◽

Als Patients ◽

Lateral Sclerosis

Abstract Background There are several studies that have discussed the efficacy of telemedicine with amyotrophic lateral sclerosis (ALS) patients; however, this approach is still preliminary in Egypt and in North Africa. The objective of the current study is to discuss current experience with telemedicine in monitoring patients in the specialized ALS clinic in Egypt. Efficacy of Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in monitoring disease progression remotely will be discussed. Results This is a prospective study. Forty-three ALS patients were included in this study in the period between July 1, 2020, and February 6, 2021. Fifty-three telemedicine encounters and 13 post-telemedicine office visits were available. None of the participating patients had COVID-19 infection. Eight patients showed decline in ALSFRS score. ALSFRS-R score reported during telemedicine encounters was confirmed during office visits. Three bulbar onset ALS patients had gastrostomy, and 2 bulbar onset ALS patients had Botox injection for drooling. All eight patients with declining ALSFRS-R were maintained on non-invasive ventilation (NIV) based on their symptoms. Conclusion This is the first study discussing telemedicine in the field of ALS in Egypt and North Africa. ALSFRS-R showed feasibility and reliability in detecting disease progression remotely.

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