Exosome microRNAs in Amyotrophic Lateral Sclerosis: A Pilot Study

The pathogenesis of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease, remains undisclosed. Mutations in ALS related genes have been identified, albeit the majority of cases are unmutated. Clinical pathology of ALS suggests a prion-like cell-to-cell diffusion of the disease possibly mediated by exosomes, small endocytic vesicles involved in the propagation of RNA molecules and proteins. In this pilot study, we focused on exosomal microRNAs (miRNAs), key regulators of many signaling pathways. We analyzed serum-derived exosomes from ALS patients in comparison with healthy donors. Exosomes were obtained by a commercial kit. Purification of miRNAs was performed using spin column chromatography and RNA was reverse transcribed into cDNA. All samples were run on the miRCURY LNATM Universal RT miRNA PCR Serum/Plasma Focus panel. An average of 29 miRNAs were detectable per sample. The supervised analysis did not identify any statistically significant difference among the groups indicating that none of the miRNA of our panel has a strong pathological role in ALS. However, selecting samples with the highest miRNA content, six biological processes shared across miRNAs through the intersection of the GO categories were identified. Our results, combined to those reported in the literature, indicated that further investigation is needed to elucidate the role of exosome-derived miRNA in ALS.

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Monocyte-Derived Macrophages Contribute to Chitinase Dysregulation in Amyotrophic Lateral Sclerosis: A Pilot Study

Frontiers in Neurology ◽

10.3389/fneur.2021.629332 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nayana Gaur ◽

Elena Huss ◽

Tino Prell ◽

Robert Steinbach ◽

Joel Guerra ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Immune System ◽

Pilot Study ◽

Temporal Expression ◽

Chronic Inflammatory Response ◽

Chronic Neuroinflammation ◽

Culture Duration ◽

Chitinase Production ◽

Als Patients ◽

Lateral Sclerosis

Neuroinflammation significantly contributes to Amyotrophic Lateral Sclerosis (ALS) pathology. In lieu of this, reports of elevated chitinase levels in ALS are interesting, as they are established surrogate markers of a chronic inflammatory response. While post-mortem studies have indicated glial expression, the cellular sources for these moieties remain to be fully understood. Therefore, the objective of this pilot study was to examine whether the peripheral immune system also contributes to chitinase dysregulation in ALS. The temporal expression of CHIT1, CHI3L1, and CHI3L2 in non-polarized monocyte-derived macrophages (MoMas) from ALS patients and healthy controls (HCs) was examined. We demonstrate that while CHIT1 and CHI3L1 display similar temporal expression dynamics in both groups, profound between-group differences were noted for these targets at later time-points i.e., when cells were fully differentiated. CHIT1 and CHI3L1 expression were significantly higher in MoMas from ALS patients at both the transcriptomic and protein level, with CHI3L1 levels also being influenced by age. Conversely, CHI3L2 expression was not influenced by disease state, culture duration, or age. Here, we demonstrate for the first time, that in ALS, circulating immune cells have an intrinsically augmented potential for chitinase production that may propagate chronic neuroinflammation, and how the ageing immune system itself contributes to neurodegeneration.

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Prognosis of amyotrophic lateral sclerosis with cognitive and behavioural changes based on a sixty-month longitudinal follow-up

PLoS ONE ◽

10.1371/journal.pone.0253279 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0253279

Author(s):

Shan Ye ◽

Pingping Jin ◽

Lu Chen ◽

Nan Zhang ◽

Dongsheng Fan

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Survival Time ◽

Progression Rate ◽

Behavioural Changes ◽

Significant Difference ◽

Long Term Follow Up ◽

Behaviour Changes ◽

Als Patients ◽

Lateral Sclerosis

Objective Approximately 50% of amyotrophic lateral sclerosis (ALS) patients have cognitive and behavioural dysfunction in varying degrees and forms. Previous studies have shown that cognitive and behavioural changes may indicate a poor prognosis, and cognitive function gradually deteriorates over the course of disease, but the results of different studies have been inconsistent. In addition, there are relatively limited long-term follow-up studies tracking death as an endpoint. The purpose of this study was to investigate the clinical prognostic characteristics of ALS patients with cognitive behavioural changes through long-term follow-up in a cohort. Methods A total of 87 ALS patients from 2014 to 2015 in the Third Hospital of Peking University were selected and divided into a pure ALS group, an ALS with behavioural variant of frontotemporal dementia (ALS-bvFTD) group, and an ALS with cognitive and behaviour changes group. All patients were followed up for 60 months. The main end point was death and tracheotomy. Results There was no significant difference in survival curve between pure ALS and ALS with cognitive and behavioural change group, but the survival time of ALS-bvFTD group was significantly lower than the other two groups (P < 0.001). For those who was followed up to the endpoint, the survival time of the ALS-bvFTD group was significantly shorter than that of the pure ALS group (t = 5.33, p < 0.001) or the ALS with cognitive and behaviour changes group (t = 4.25, p < 0.001). The progression rate of ALS Functional Rating Scale–Revised (FRS-R) scores from recruitment to endpoint was significantly faster in the ALS-bvFTD group than in the pure ALS group (z = 2.68, p = 0.01) or the ALS with cognitive and behavioural changes group (z = 2.75, p = 0.01). There was no significant difference in survival time (t = 0.52, P = 0.60) or FRS-R score progression rate (z = 0.31, p = 0.76) between the pure ALS group and the ALS with cognitive and behavioural changes group. The total Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) score was positively correlated with survival time (r = 0.38, p = 0.01). Conclusion ALS-bvFTD patients have shorter survival time. The total ECAS score may be correlated with survival time.

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Brainstem Involvement in Amyotrophic Lateral Sclerosis: A Combined Structural and Diffusion Tensor MRI Analysis

Frontiers in Neuroscience ◽

10.3389/fnins.2021.675444 ◽

2021 ◽

Vol 15 ◽

Author(s):

Haining Li ◽

Qiuli Zhang ◽

Qianqian Duan ◽

Jiaoting Jin ◽

Fangfang Hu ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Correlation Analysis ◽

Disease Severity ◽

Structural Changes ◽

Diffusion Tensor ◽

Healthy Controls ◽

Significant Difference ◽

Als Patients ◽

And Diffusion ◽

Lateral Sclerosis

IntroductionThe brainstem is an important component in the pathology of amyotrophic lateral sclerosis (ALS). Although neuroimaging studies have shown multiple structural changes in ALS patients, few studies have investigated structural alterations in the brainstem. Herein, we compared the brainstem structure between patients with ALS and healthy controls.MethodsA total of 33 patients with ALS and 33 healthy controls were recruited in this study. T1-weighted and diffusion tensor imaging (DTI) were acquired on a 3 Tesla magnetic resonance imaging (3T MRI) scanner. Volumetric and vertex-wised approaches were implemented to assess the differences in the brainstem’s morphological features between the two groups. An atlas-based region of interest (ROI) analysis was performed to compare the white matter integrity of the brainstem between the two groups. Additionally, a correlation analysis was used to evaluate the relationship between ALS clinical characteristics and structural features.ResultsVolumetric analyses showed no significant difference in the subregion volume of the brainstem between ALS patients and healthy controls. In the shape analyses, ALS patients had a local abnormal surface contraction in the ventral medulla oblongata and ventral pons. Compared with healthy controls, ALS patients showed significantly lower fractional anisotropy (FA) in the left corticospinal tract (CST) and bilateral frontopontine tracts (FPT) at the brainstem level, and higher radial diffusivity (RD) in bilateral CST and left FPT at the brainstem level by ROI analysis in DTI. Correlation analysis showed that disease severity was positively associated with FA in left CST and left FPT.ConclusionThese findings suggest that the brainstem in ALS suffers atrophy, and degenerative processes in the brainstem may reflect disease severity in ALS. These findings may be helpful for further understanding of potential neural mechanisms in ALS.

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An in-depth analysis of phosphorylated tau in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid

10.1101/2020.12.30.20248944 ◽

2021 ◽

Author(s):

Tiziana Petrozziello ◽

Ana C. Amaral ◽

Simon Dujardin ◽

Sali M.K. Farhan ◽

James Chan ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Cortex ◽

Molecular Mechanisms ◽

Rating Scale ◽

Phosphorylated Tau ◽

Post Mortem ◽

Significant Difference ◽

Depth Analysis ◽

Als Patients ◽

Lateral Sclerosis

AbstractAlthough the molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are not yet fully understood, recent studies have described alterations in tau protein in both sporadic and familial ALS. However, it is unclear whether alterations in tau contribute to ALS pathogenesis. Here, we leveraged the ALS Knowledge Portal and Project MinE data sets and identified specific genetic variants clustering within the microtubule-binding domain of MAPT, which were unique to ALS cases. Furthermore, our analysis in a large post-mortem cohort of ALS and control motor cortex demonstrates that although there was no significant difference in the presence of phosphorylated tau (pTau) neuropil threads and neurofibrillary tangles between the two groups, pTau-S396 and pTau-S404 mis-localized to the nucleus and synapses in ALS. This was specific to the C-terminus phosphorylation sites as there was a significant decrease in pTau-T181 in ALS synaptoneurosomes compared to controls. Lastly, while there was no change in total tau or pTau-T181 in ALS CSF, there was a decrease in pTau-T181:tau ratio in ALS CSF, as previously reported. Importantly, CSF tau levels were increased in ALS patients diagnosed with bulbar onset ALS, while pTau-T181:tau ratio was decreased in ALS patients diagnosed with both bulbar and limb onset. Additionally, there was an inverse correlation between tau levels in the CSF and the revised ALS functional rating scale (ALSFRS-R) as well as a correlation between pTau-T181:tau ratio and ALSFRS-R. While there were no longitudinal alterations in tau, pTau-T181 and pTau-T181:tau ratio, there was an increase in the rate of ALSFRS-R decline per month associated with increases in tau levels. This decline was also inversely correlated with increases in pTau-T181 in relation to tau levels. Taken together, our findings demonstrate that, like Alzheimer’s disease, hyperphosphorylated tau is mis-localized in ALS and that decreases in CSF pTau-T181 may serve as a biomarker in ALS.

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Open Randomized Clinical Trial on JWSJZ Decoction for the Treatment of ALS Patients

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/347525 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Weidong Pan ◽

Xiaojing Su ◽

Jie Bao ◽

Jun Wang ◽

Jin Zhu ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Control Group ◽

Efficacy And Safety ◽

Significant Difference ◽

Als Patients ◽

And Control ◽

Lateral Sclerosis ◽

Basic Treatment

Objective. To investigate the efficacy and safety of the traditional Chinese medicine Jiawei Sijunzi (JWSJZ) decoction for the treatment of patients with amyotrophic lateral sclerosis (ALS).Methods. Forty-eight patients with ALS were divided into a JWSJZ group (n=24) and a control group (n=24) using a randomized number method. Together with the basic treatment for ALS, JWSJZ decoction was added to the treatment regimen of patients in the JWSJZ group or Riluzole was administered to the control group for 6 months. Neurologists evaluated the treated and control patients using the ALS functional rating scale (ALSFRS) before, 3 and 6 months after starting the additional treatments.Results. The ALSFRS scores in both groups were lower 3 and 6 months after treatment than before. There was a significant difference at 6 months after treatment between the subgroups of patients with ALS whose limbs were the initial site of attack. No serious adverse effects were observed in the JWSJZ group.Conclusion. JWSJZ decoction may be a safe treatment for ALS, and may have delayed the development of ALS, especially in the subgroup of patients in whom the limbs were attacked first when compared with Riluzole treatment.

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Electrophysiological Characterization of C9ORF72-Associated Amyotrophic Lateral Sclerosis: A Retrospective Study

European Neurology ◽

10.1159/000505777 ◽

2019 ◽

Vol 82 (4-6) ◽

pp. 106-112 ◽

Cited By ~ 1

Author(s):

Antoine Pegat ◽

Françoise Bouhour ◽

Kevin Mouzat ◽

Christophe Vial ◽

Benoit Pegat ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Sensory Neuropathy ◽

Mean Values ◽

Cognitive Domains ◽

Sensory Conduction ◽

Significant Difference ◽

The Mean ◽

Electrophysiological Characterization ◽

Als Patients ◽

Lateral Sclerosis

Objective: C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine whether C9ORF72-associated ALS (C9-ALS) patients present distinctive electrophysiological characteristics that could differentiate them from non C9ORF72-associated ALS (nonC9-ALS) patients. Methods: Clinical and electrodiagnostic data from C9-ALS patients and nonC9-ALS patients were collected retrospectively. For electroneuromyography, the mean values of motor conduction, myography, and the mean values of sensory conduction were considered. Furthermore, the proportion of ALS patients with electrophysiological sensory neuropathy was determined. Results: No significant difference was observed between 31 C9-ALS patients and 22 nonC9-ALS patients for mean motor conduction and myography. For sensory conduction analyses, mean sensory conduction was not significantly different between both groups. In total, 38% of C9-ALS patient and 21% of nonC9-ALS patients presented electrophysiological sensory neuropathy (p = 0.33). In C9-ALS patients with electrophysiological sensory neuropathy, 80% (8/10) were male and 67% (6/9) presented spinal onset compare to 25% (4/16, p = 0.014) male and 25% (4/16, p = 0.087) with spinal onset in those without electrophysiological sensory neuropathy. Conclusion: Although not different from nonC9-ALS, these results suggest that sensory involvement is a frequent feature of C9-ALS patients, expanding the phenotype of the disease beyond the motor and cognitive domains.

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A Phase 2A randomized, double-blind, placebo-controlled pilot trial of GM604 in patients with Amyotrophic Lateral Sclerosis (ALS Protocol GALS-001) and a single compassionate patient treatment (Protocol GALS-C)

F1000Research ◽

10.12688/f1000research.10519.1 ◽

2017 ◽

Vol 6 ◽

pp. 230 ◽

Cited By ~ 6

Author(s):

Mark Kindy ◽

Paul Lupinacci ◽

Raymond Chau ◽

Tony Shum ◽

Dorothy Ko

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pilot Trial ◽

Disease Onset ◽

Treatment Protocol ◽

Double Blind ◽

Insulin Receptor Tyrosine Kinase ◽

Double Blind Placebo ◽

Significant Difference ◽

Als Patients ◽

Lateral Sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options. Genervon has discovered and developed GM604 (GM6) as a potential ALS therapy. GM6 has been modeled upon an insulin receptor tyrosine kinase binding motoneuronotrophic factor within the developing central nervous system. Methods This was a 2-center phase 2A, randomized, double-blind, placebo-controlled pilot trial with 12 definite ALS patients diagnosed within 2 years of disease onset. Patients received 6 doses of GM604 or placebo, administered as slow IV bolus injections (3x/week, 2 consecutive weeks). Objectives were to assess the safety and efficacy of GM604 based on ALSFRS-R, FVC and selected biomarkers (TDP-43, Tau and SOD1, pNFH). This report also includes results of compassionate treatment protocol GALS-C for an advanced ALS patient. Results Definite ALS patients were randomized to one of two treatment groups (GM604, n = 8; placebo, n = 4). 2 of 8 GM604-treated patients exhibited mild rash, but otherwise adverse event frequency was similar in treated and placebo groups. GM604 slowed functional decline (ALSFRS-R) when compared to a historical control (P = 0.005). At one study site, a statistically significant difference between treatment and control groups was found when comparing changes in respiratory function (FVC) between baseline and week 12 (P = 0.027). GM604 decreased plasma levels of key ALS biomarkers relative to the placebo group (TDP-43, P = 0.008; Tau, P = 0.037; SOD1, P = 0.009). The advanced ALS patient in compassionate treatment demonstrated improved speech, oral fluid consumption, mouth suction with GM604 treatment and biomarker improvements. Conclusions We observed favorable shifts in ALS biomarkers and improved functional measures during the Phase 2A study as well as in an advanced ALS patient. Although a larger trial is needed to confirm these findings, the present data are encouraging and support GM604 as an ALS drug candidate.

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Longitudinal Timed Up and Go Assessment in Amyotrophic Lateral Sclerosis: A Pilot Study

European Neurology ◽

10.1159/000516772 ◽

2021 ◽

pp. 1-5

Author(s):

Eglė Sukockienė ◽

Ruxandra Iancu Ferfoglia ◽

Antoine Poncet ◽

Jean-Paul Janssens ◽

Gilles Allali

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pilot Study ◽

Walking Ability ◽

University Hospitals ◽

Timed Up And Go ◽

Progressive Loss ◽

Bulbar Onset ◽

Als Patients ◽

Lateral Sclerosis

Progressive loss of walking ability in amyotrophic lateral sclerosis (ALS) has been scarcely studied as a potential predictive factor for survival in motor neuron disease. We aimed to assess the progression of gait decline and its association with mortality in ALS using the Timed Up and Go test (TUG). Patients were followed up prospectively at the Centre for ALS and Related Disorders in Geneva University Hospitals between 2012 and 2016. The TUG was performed at baseline and subsequent evaluations occurred every 3 months. At inclusion, patients were classified as unable to perform the TUG, “slow TUG” (>10.6 s), and “fast TUG” (≤10.6 s). In total, 68 patients with ALS (mean ± SD age: 68.6 ± 11.9 years; 50% female) were included. Baseline TUG was negatively correlated with the total ALSFRS-R score (r = −0.63, p < 0.001). At baseline, ALS patients with bulbar onset performed the TUG faster (9.9 ± 3.7 s) than the non-bulbar ones (17.3 ± 14.9 s, p = 0.008). Thirty of 68 (44%) patients died by the end of the follow-up period. The TUG performance at the first visit did not predict mortality. While we did not find any association with mortality in ALS and gait quantification, the TUG was feasible in a majority of ALS patients, was correlated with functional status, and could be of interest in the follow-up of non-bulbar ALS patients.

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The Effects of Sa-Am Acupuncture Treatment on Respiratory Physiology Parameters in Amyotrophic Lateral Sclerosis Patients: A Pilot Study

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/506317 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Sangmi Lee ◽

Sungchul Kim

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pilot Study ◽

Pulse Rate ◽

Acupuncture Treatment ◽

Respiratory Physiology ◽

Future Research ◽

Acupuncture Stimulation ◽

Als Patients ◽

Physiology Parameters ◽

Lateral Sclerosis

Respiratory dysfunction and complications are the most common causes of death in amyotrophic lateral sclerosis. This is a pilot study to observe the changes in respiratory physiology parameters after Sa-am acupuncture treatment. Eighteen ALS patients received Sa-am acupuncture treatment twice a day for 5 days. The EtCO2, SpO2, RR, and pulse rate were measured for 15 min before and during treatment, using capnography and oximetry. Correlation of K-ALSFRS-R scores against measured parameters showed that patients who had high K-ALSFRS-R scores had greater changes in pulse rate after acupuncture stimulation; they also showed a decrease in EtCO2, RR, and pulse rate and an increase in SpO2. A comparison of the mean values of these different parameters before and after Sa-am acupuncture stimulation revealed statistically significant differences (P<0.05) in SpO2and pulse rate, but none in EtCO2and RR. Sa-am acupuncture treatment on ALS patients seems to be more effective in the early stages of the disease. In light of increased SpO2values, Sa-am acupuncture appears to have a greater effect on inspiration rather than on expiration. As a pilot study of acupuncture on ALS patients, this study could be used as a basis for future research.

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Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis

Behavioural Neurology ◽

10.1155/2018/2635202 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Cinzia Femiano ◽

Francesca Trojsi ◽

Giuseppina Caiazzo ◽

Mattia Siciliano ◽

Carla Passaniti ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Diffusion Tensor Imaging ◽

Diffusion Tensor ◽

Anterior Cingulate ◽

Behavioral Impairment ◽

Brain Areas ◽

Significant Difference ◽

Als Patients ◽

Lateral Sclerosis ◽

Diffusion Tensor Imaging Dti

Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in King’s clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p<.05, threshold-free cluster enhancement (TFCE) corrected] in the corpus callosum and in bilateral anterior cingulate cortices. Self-rated Apathy Evaluation Scale (AES) scores and self-rated apathy T-scores of the Frontal Systems Behavior (FrSBe) scale were found inversely correlated to FA measures (p<.05, TFCE corrected) in widespread white matter (WM) areas, including several associative fiber tracts in the frontal, temporal, and parietal lobes. These results point towards an early microstructural degeneration of brain areas biologically involved in cognition and behavior regulation in ALS. Moreover, the significant correlations between apathy and DTI measures in several brain areas may suggest that subtle WM changes may be associated with mild behavioral symptoms in ALS even in the absence of overt cognitive and behavioral impairment.

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