Serious Game-Based Training for Improved Control of a Temporalis Electromyography Interface for Controlling Powered Wheelchairs.

Objective To evaluate the value of neurophysiological index (NI) in evaluating the rate of progression of amyotrophic lateral sclerosis (ALS). Methods Forty-eight patients with ALS were enrolled in Zhongda Hospital of Southeast University from January 2010 to August 2016, of whom 36 patients met the ALS definite diagnostic criteria, 12 patients met the ALS probable diagnostic criteria (following study confirmed those patients met the ALS definite diagnostic criteria), including 8 bulbar-onset and 40 upper extremity onset forms of the disease. Fifty-four age- and sex-matched healthy subjects served as controls. After evaluated by the ALS Functional Rating Scale-revised (ALSFRS-R), all subjects underwent electrophysiological examination in the Electromyography Lab of the hospital. The rate of disease progression (ΔFS) =48-total ALSFRS-R score at initial visit/symptom duration (months). The relevance between the complex muscle action potential (CMAP), F frequency, distal motor latency (DML), NI and the ΔFS was investigated respectively. Results In ALS group, the ALSFRS-R score was 14.56±10.10, the duration from onset to diagnosis was (14.56±10.10) months, and the ΔFS was 1.54±1.18 per month. The median nerve NI in ALS group was 0.60±0.76, in control group was 2.56±0.78, with statistically significant difference between two groups (t=-12.5, P<0.01). The ulnar nerve NI in ALS group was 0.70±0.55, in control group was 0.96±0.10, also with statistically significant difference between two groups (t=-0.31, P=0.003). The median nerve NI and ulnar nerve NI both were negatively correlated with ΔFS (r=-0.63, P=0.000; r=-0.506, P=0.007). The ΔFS was exponentially based on median nerve NI (R2=0.668, P<0.01). Conclusion NI is an objective electrophysiological index, which could be used to evaluate the rate of disease progression in ALS, and to evaluate the prognosis of the disease. Key words: Amyotrophic lateral sclerosis; Nerve conduction; Neurophysiological index; Prognosis

In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1). This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels. In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01). Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.

Clawson LL, Cudkowicz M, Krivickas L, Brooks BR, Sanjak M, Allred P, Atassi N, Swartz A, Steinhorn G, Uchil A, Riley KM, Yu H, Shoenfeld DA, Maragakis NJ. A randomized controlled trial of resistance and endurance exercise in amyotrophic lateral sclerosis. Amyotrophic Lateral Scler Frontotemporal Degene. 2018;19(3–4):250–8.Amyotrophic lateral sclerosis (ALS) is classified as a neurodegenerative disease that results in destruction of motor neurons in the brain and spinal cord (1). The cause of this disease is unknown, with 90% of all cases being nonfamilial (1). As ALS progresses, it results in cachexia, loss of muscle mass and movement coordination, paralysis, and eventual death (1). It is estimated that 30,000 people in the US (1) and 1,400 people in Australia (2) are living with ALS.According to the American Academy of Neurology the current standard of care for persons with ALS includes static stretching and passive range of motion to offset muscle and joint stiffness caused by neurologic decline (3). Low powered studies and conflicting research results of the effect of resistance (weights lifting) and/or aerobic exercise on ALS have led to difficulty determining recommendations for these modes of exercise (3). Some researchers indicate that vigorous aerobic or intense resistance training may increase the risk of (4) or exacerbate the progression (3) of ALS. Because of this, some clinicians instruct patients to avoid these forms of exercise. On the contrary, authors of several studies in mice (5) and humans (6) suggest resistance and aerobic exercise have multiple benefits for ALS, including delayed onset of symptoms, slowed progression, and improved quality of life, without being a major risk factor (7). The aim of this study was to determine the tolerance and compliance of exercise when comparing resistance, aerobic, and stretching or passive range of motion exercises in persons with ALS.This 24-week, randomized controlled trial included persons with ALS who met these inclusion criteria: (a) classified as having lab-supported probable or definite ALS, confirmed by a neurologist and (b) willingness to participate in this study. Exclusion criteria were not mentioned. Due to difficulty with the recruitment of persons with ALS who were willing to perform exercises, this study began in April 2012, with the last participant enrolled in September 2015.Fifty-nine participants were randomly assigned to resistance training (n = 21), aerobic exercise (n = 18), or static stretching or passive range of motion [S-ROM] (n = 20). Tolerability was defined as each participant completing ≥50% of total repetitions assigned for resistance training and S-ROM and ≥50% of aerobic exercise duration programmed at a specific heart rate and perceived exertions scale (Borg 6–20) rating. Compliance was defined as each participant attempting ≥50% of all exercise sessions for the 24-week period. Broad compliance measures were implemented with anticipation of rapid progression of ALS and inability to perform higher intensity or longer duration exercise. As a result, broad compliance measures afforded participants greater consistency with exercise completion at each session. To improve retention and avoid travel to treatment center, home-based exercise was programmed for all participants. The participants' “home exercise partner” was initially trained by a physical therapist, and appropriate exercise form was evaluated at follow-up visits throughout the course of the intervention. Outcome measures included exercise compliance and tolerance with secondary measures, including ALS Functional Rating Scale-Revised, ALS Scale for Quality of Life-Revised (3), Fatigue Severity Scale, Ash-worth Spasticity Scale (6), and Visual Analog Scale. Follow-up measures were taken at weeks 12 and 24. Training logs and teleconferences were used to track at-home exercise compliance and tolerance.All groups performed 3 exercise sessions per week. Resistance training included 2 sets of 8 repetitions with use of ankle or wrist weights. Initial intensity was 40% 1 repetition maximum (1RM) and was increased to 50% 1RM at week 4 and 70% 1RM at week 6. 1RM testing was conducted at baseline. Aerobic exercise included the use of a minicycle with 10 min of upper and lower body cycling, respectively, at 50%–70% heart rate reserve and 13–15 on the Borg scale. S-ROM exercise included 4 sets of 30-second static stretches for each exercise. For a list of exercises, see the Supplemental Material (https://www.tandfonline.com/doi/suppl/10.1080/21678421.2017.1404108).Analysis of all primary and secondary outcomes was conducted at 12 and 24 weeks. Over the course of the study, there were 4 serious adverse events resulting in withdrawal from the study, none of which were deemed a direct result of the exercise intervention or resulted in death. In addition, another 11 participants were lost to follow up (n = 4), co-enrollment in another study (n = 1), difficulty with travel (n = 1), or complication associated with disease progression (n = 2). Minor adverse events that are frequently seen in persons with ALS included musculoskeletal injury, fatigue, and falling, which did not differ between the groups.When assessing the proportion of participants that were able to tolerate exercise, the S-ROM, resistance, and aerobic groups were 77%, 65%, and 51% compliant. These results indicated all 3 modes of exercise are well tolerated by persons with ALS and safe to perform, with greatest compliance occurring in the S-ROM and resistance groups. There were no differences at 12 or 24 weeks regarding any of the secondary measures, which suggests that resistance and aerobic training did not exacerbate or cause accelerated progression of disease, reduce quality of life, or increase fatigue in this sample of participants.This is one of the first studies to demonstrate that resistance and aerobic exercise is safe and well tolerated for persons with ALS, and compliance with resistance training is comparable with standard care (S-ROM). The findings of this study are supported by previous researchers (6,8) that demonstrate short-term improvement in disability associated with supervised resistance and aerobic training. It is possible that differences in exercise adherence can be attributed to the intensity parameters being too low for resistance training or too high for aerobic training, resulting in lower compliance rates associated with the S-ROM, respectively. Future researchers will need to focus on specific frequency, intensity, type, and volume of exercise programming for the management of ALS. Although the clinical exercise physiologist should interpret the results of this study with caution, the use of resistance and aerobic training should be considered as a management technique for patients diagnosed with ALS.Quinn L, Hamana K, Kelson M, Dawes H, Collett J, Townsen J, Raymund R, van der Plas AA, Reilmann R, Frich JC, Rickards H, Rosser A, Busse M. A randomized, controlled trial of a multi-modal exercise intervention in Huntington's disease. Parkinsonism Relat Disord. 2016;31:4–52.Huntington's disease (HD) is a genetically linked neurodegenerative disease that is progressive and results in neuronal damage to the substantia nigra and cerebral cortex of the brain (1). HD is associated with nonmotor symptoms such as cognitive impairment, dementia, memory loss, and disorientation, as well as motor symptoms including chorea (irregular or rapid) and athetosis (slow or writhing involuntary) movements of the hands, feet, face, and trunk (1). Currently, there are approximately 30,000 people in the US (1) and 1,500 people in Australia (2) who are living with HD.The effectiveness of exercise as a management technique for HD is a relatively new research focus with limited studies. It is suggested that multimodal rehabilitation programs can improve physical function, quality of life (3), and possibly cognition (4) in persons with HD. Many challenges exist with determining the effectiveness of exercise-based interventions on HD, including level of supervision, appropriately programmed intensity, variability of cognitive impairment, exercise preference or tolerance, and comfort with exercise settings (5,6). These factors can lead to reduced initiation and adherence to exercise for persons with HD. Therefore, the aim of this study is to determine the effectiveness of a multimodal exercise program on persons with mild to moderate HD to determine safety, feasibility regarding retention and adherence, and improvement of physical fitness, motor control, physical function, and cognition.This was a randomized, controlled, multicenter trial, that assigned 32 of 312 screened participants to an exercise (n = 17) or control (n = 15) group for a 12-week intervention and 26-week follow up. Inclusion criteria were (a) genetically confirmed cases of HD, (b) ≥18 years of age, and (c) stable medication regime of antichoreic drugs for 4 weeks. Participants were excluded if they were (a) unable to use an exercise bike, (b) had psychological or physical limitation precluding exercise testing, and (c) currently in an exercise program. All participants who met inclusion criteria were screened for cardiovascular risk factors and underwent electrocardiogram testing to ensure safety with initiation of exercise.The control (CT) group was instructed to carry on with normal activity for the full duration of the intervention. Participants in the exercise (EX) group participated in three 50-min exercise sessions per week for a total of 12 weeks. Follow-up assessment occurred at week 13 and was compared with the baseline. Exercise included 25 min of cycling at 55%–85% age-predicted maximum heart rate (APMHR), 10–15 min of resistance training (2 sets of 15 repetitions), and 5 min of static stretching. For full details on the exercise program, see the Supplemental Material (https://www.prd-journal.com/article/S1353-8020(16)30243-7/fulltext#supplementaryMaterial). Participants could choose between their home or a medical fitness center to perform the exercise. An exercise professional provided gym-based supervision and at-home exercise for all 3 sessions during weeks 1–2, which was then tapered to 2 sessions for weeks 3–6, and 1 session for the final 6 weeks.Primary outcome measures included retention (completion of intervention) and adherence (completion of sessions), which was predetermined as &gt;75% of supervised and unsupervised sessions and maintaining APMHR intensities for &gt;75% (19/25 min) of the cycling duration. A series of secondary measures were also collected at baseline and follow-up assessment to determine improvement in motor control, quality of life, and physical and cognitive function (7–10).Three participants from the EX group dropped out before the 13-week assessment due to concomitant conditions, and 10 (n = 5 EX and n = 5 CT) were unable to be contacted at the 26-week period. Two serious adverse events occurred in the CT group, both attempted suicides, with 1 possibly being related to the week 13 assessment. A total of 97% of the EX group completed the intervention. Ninety-three percent of the EX group were able to complete the required sessions of the intervention, with only 75% achieving APMHR at each exercise session. Blunted heart rate response can be attributed to autonomic dysfunction commonly associated with HD, resulting in the inability to reach a predetermined percentage for APMHR (1). The EX and CT groups showed no differences in fall occurrence, suggesting that supervised exercise does not incur a greater fall risk in this population.The EX group improved aerobic fitness (VO2 MAX), motor function, and reduced body weight compared with the CT group. A reduced body weight may not be considered a positive finding because HD can lead to rapid weight loss in some people, resulting in cachexia and negative health outcomes (11). Follow-up assessment at 26 weeks indicated that all EX participants returned to low levels of physical activity after the intervention was terminated, and there were no differences in measured health outcome between groups.This is the first study to demonstrate that a multimodal exercise program is safe and that persons with mild to moderate HD can adhere to exercise with and without supervision and in different settings. The authors of this study showed improvement in aerobic fitness and motor control, but no improvement in strength, physical function, or cognition, which can all reduce quality of life in persons with HD (3). The exclusion of those with cognitive deficit and mental health disease, which is commonly associate with HD, may have resulted in reduced applicability of this study. The resistance training protocol may have used an intensity and/ or volume that was too low for improvement in strength. Future researchers might investigate the effects of resistance versus aerobic training and allow for a more robust sample of participants with and without HD-related cognitive impairment. The clinical exercise physiologist should encourage persons with HD to remain physically active using a multimodal program when safe and appropriate for an individual.The current Research Highlights editor would like to thank the JCEP Editorial Board for the opportunity to contribute this journal by authoring the Research Highlights for the past several years. We welcome Dr. Elizabeth O'Neill, DPE (Springfield College, Springfield, MA) as the new Research Highlights editor.

To determine the prevalence of depression, to identify correlated factors for depression, and to explore the impact on the progression or survival of amyotrophic lateral sclerosis (ALS) by depression in a Chinese population. A total of 166 ALS patients were recruited. Diagnosis of depression disorders and the severity of depression were established by using the fourth diagnostic and statistical manual of mental disorders, Hamilton Depression Rating Scale-24 items (HDRS-24) and Beck Depression Inventory (BDI). Major depression was found in 15 patients (9.6%). The multiple regression analysis showed that a lower ALS Functional Rating Scale-Revised (ALSFRS-R) score was correlated with increasing HDRS scores and BDI scores (P=0.018 and P=0.012). No significant difference in the median survival time between ALS patients with and without depression was revealed by Kaplan-Meier analysis (log-rank P=0.282). Cox hazard model showed that the presence of depression in ALS was unrelated to the survival, while the severity of depression in ALS was correlated with the survival. The presence and severity of depression in ALS did not correlate with the progression of ALS. Major depression in ALS is uncommon. Depression evaluation should be given to ALS patients, especially those with lower ALSFRS-R score. The severity of depression may be associated with the survival; however, depression does not worse the progression of ALS.

Rationale: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the central nervous system (CNS). Non-neuronal cells, particularly astrocytes, have been recognized as pivotal contributors to ALS onset and progression. However, the underlying mechanisms of interactions between astrocytes and motor neurons during ALS remain unclear. Recent studies have identified the neuronal Hippo kinase mammalian sterile 20-like kinase 1 (MST1) as a key regulator of neurodegeneration in ALS. Yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is predominantly expressed in astrocytes. However, the role of astrocytic YAP in ALS and its underlying mechanisms remain unexplored.Methods: To evaluate the function of YAP in ALS, we established a C9orf72-poly-GA mouse model (ALS mice) via intracerebroventricular injection of AAV viruses. Furthermore, mice with conditional knockout (CKO) of YAP in astrocytes (YAPGFAP-CKO mice) were generated and then YAPGFAP-CKO ALS mice and their littermate controls (YAPf/f ALS mice) were used as experimental subjects. Behavioral tests, immunostaining, Nissl staining, quantitative real-time PCR (qPCR), and Western blotting were used to assess the effects of astrocytic YAP deletion in ALS progression. In addition, we investigated the role and mechanism of astrocytic YAP in the pathogenesis of ALS by integrating RNA sequencing (RNA-seq) from primary cultured astrocytes with single-nucleus transcriptomic (snRNA-seq) from C9orf72-ALS/FTD patients. Then, in vitro experiments including primary cultured astrocytes and neurons were used to further elucidate the potential molecular mechanism of astrocytic YAP in ALS. Finally, we evaluated the therapeutic effects of the excitatory amino acid transporter-2 (EAAT2) activator LDN-212320 and the Hippo kinase MST1/2 inhibitor XMU-MP-1 as candidate treatments for ALS.Results: We found that YAP was upregulated and activated specifically in astrocytes, but not in neurons or microglia, within the motor cortex of ALS mice. Conditional knockout of YAP in astrocytes exacerbated motor deficits, neuronal loss, pathological translocation of TDP-43, inflammatory infiltration, and reduced astrocytic proliferation in ALS mice. Mechanistically, Wnts secreted by degenerating neurons and astrocytes activated YAP/β-catenin signaling and further promoted the expression of EAAT2 in astrocytes, which prevented neuronal glutamate excitotoxicity, neuronal loss, and motor dysfunction in ALS mice. Interestingly, treatment with LDN-212320 promoted EAAT2 expression and partially restored motor deficits and neuronal loss in YAPGFAP-CKO ALS mice. Finally, activation of YAP by XMU-MP-1 upregulated β-catenin and EAAT2 expression, and partially alleviated motor deficits and neurodegeneration in ALS mice.Conclusions: These results identify an unrecognized mechanism of self-protection in degenerating neurons mediated by astrocytic YAP through Wnts/β-catenin/EAAT2 signaling to prevent glutamate excitotoxicity of neurons in ALS mice, and provide a novel drug target for ALS.

Previous studies have reported distinct serological profiles of lipid, urate and ferritin in Western patients with amyotrophic lateral sclerosis (ALS). We aimed to examine the levels of these serological factors and their relationship to disease progression in Japanese ALS patients. Ninety-two patients with definite or probable ALS who fulfilled the revised El Escorial criteria were analyzed for clinical and serological variables. Serological data at the time diagnosed with ALS were compared to those of 92 age/sex/body mass index-matched healthy controls. Compared to controls, urate and creatinine (Cr) levels were decreased and ferritin levels were increased significantly in sera of male and female patients with ALS. Significant increases of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were found in female ALS patients. The annual decline of ALS Functional Rating Scale-Revised (ALS-FRS) and forced vital capacity (FVC) were inversely correlated with serum TC, LDL-C, Cr and urate levels, and were positively correlated with serum ferritin levels. Multivariate analysis showed that the rapid worsening of annual ALS-FRS and FVC was associated with serum levels of TC, LDL-C, Cr, urate and ferritin. The present study indicated that serum levels of TC, LDL-C, Cr, urate and ferritin were correlated with clinical deterioration in ALS patients. These results are similar to those in Western patients. Metabolic and nutritional conditions of lipid, urate and iron could contribute to disease progression in ALS patients. Further studies investigating high nutrition diets and iron chelation for the treatment of ALS are warranted.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease, with a 3–5-year survival from diagnosis. Possible prognostic serum biomarkers include albumin, C-reactive protein, ferritin, creatinine, uric acid, hemoglobin, potassium, sodium, calcium, glucose, and the neutrophil-to-lymphocyte ratio (NLR), a marker of subclinical inflammation. Objective: To ascertain the influence of NLR on ALS progression rate and survival. Methods: Cross-sectional multicenter study including 146 consecutive incident and prevalent patients (88 males), aged >18 years, diagnosed according to the El Escorial criteria. The exclusion criteria were: (1) patients with tracheostomy or receiving mechanical ventilation; (2) patients with percutaneous endoscopic gastrostomy; and (3) patients who did not sign the informed consent. The rate of disease progression (ΔFS score) represents the monthly decline of the ALSFRS-R score, and was computed as (48 − total ALSFRS-R at recruitment)/symptom duration in months. Patients were followed up to tracheotomy, death, or the end of the follow-up, whichever occurred first. To validate our findings, we used data retrieved from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. Results: The median disease duration was 15 (range = 2–30) months. The mean ALSFRS-R score at recruitment was 35.8 ± 8.0 (range: 10–48), and the median ΔFS was 0.66 (range: 0–5.33). Age at onset, at diagnosis, and at recruitment were significantly lower in the lowest NLR tertile. NLR values positively correlated with ΔFS values (r = 0.28): the regression slope of NLR (log-values) was 0.60 (p < 0.001) before and 0.49 (p = 0.006) after adjustment for age at recruitment. The ΔFS score progressively increased from the lowest to the highest NLR tertile: 0.35 (IQR: 0.18–0.93), 0.62 (IQR: 0.25–1.09), and 0.86 (IQR: 0.53–1.92). Patients were followed for a median of 2 years. The mortality rate passed from 15.9 events per 100 person-years in patients belonging to the lowest NLR tertile to 52.8 in those in the highest tertile. The optimal cut-off value which best classified patients with the lowest and the highest mortality rate was set at the NLR value of 2.315. Indeed, the mortality rate of patients with an NLR value above such cut-off was twice the mortality rate of patients with a value below the cut-off (age adjusted hazard ratio (HR): 2.16, 95% confidence interval (CI): 1.32–3.53). In the PRO-ACT validation sample, patients with an NLR value above the cut-off consistently had a higher mortality rate than those with a value below the cut-off (age adjusted HR: 1.17, 95%CI: 1.01–1.35). Conclusions: NLR could be a candidate easy, fast, and low-cost marker of disease progression and survival in ALS. It may be associated with low-grade inflammation either as a direct mirror of the pathological process of disease progression, or as a consequence of neuronal death (reverse causation). However, prospective studies are needed to understand whether NLR changes during the course of the disease, before using it to monitor disease progression in ALS.

Mutations in copper-zinc superoxide dismutase (SOD1) have been linked to a subset of familial amytrophic lateral sclerosis (fALS), a fatal neurodegenerative disease characterized by progressive motor neuron death. An increasing amount of evidence supports that mitochondrial dysfunction and apoptosis activation play a critical role in the fALS etiology, but little is known about the mechanisms by which SOD1 mutants cause the mitochondrial dysfunction and apoptosis. In this study, we use proteomic approaches to identify the mitochondrial proteins that are altered in the presence of a fALS-causing mutant G93A-SOD1. A comprehensive characterization of mitochondrial proteins from NSC34 cells, a motor neuron-like cell line, was achieved by two independent proteomic approaches. Four hundred seventy unique proteins were identified in the mitochondrial fraction collectively, 75 of which are newly discovered proteins that previously had only been reported at the cDNA level. Two-dimensional gel electrophoresis was subsequently used to analyze the differences between the mitochondrial proteomes of NSC34 cells expressing wild-type and G93A-SOD1. Nine and 36 protein spots displayed elevated and suppressed abundance respectively in G93A-SOD1-expressing cells. The 45 spots were identified by MS, and they include proteins involved in mitochondrial membrane transport, apoptosis, the respiratory chain, and molecular chaperones. In particular, alterations in the post-translational modifications of voltage-dependent anion channel 2 (VDAC2) were found, and its relevance to regulating mitochondrial membrane permeability and activation of apoptotic pathways is discussed. The potential role of other proteins in the mutant SOD1-mediated fALS is also discussed. This study has produced a short list of mitochondrial proteins that may hold the key to the mechanisms by which SOD1 mutants cause mitochondrial dysfunction and neuronal death. It has laid the foundation for further detailed functional studies to elucidate the role of particular mitochondrial proteins, such as VDAC2, in the pathogenesis of familial ALS.

ObjectiveTo investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).MethodsA cross-sectional study involving 136...

To study the effects of head injury on disease progression and on neuropathologic outcomes in amyotrophic lateral sclerosis (ALS). Patients with ALS were surveyed to obtain head injury history, and medical records were reviewed. Linear regression was performed to determine if head injury was a predictor for mean monthly decline of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R), while controlling for confounders. Head injury history was obtained from family members of ALS autopsy cases. The frequency of tau proteinopathy, brain TDP-43 inclusions, and pathologic findings of Alzheimer disease (AD) were examined in ALS cases with head injury compared to cases without. Logistic regression was performed with each neuropathologic diagnosis as an outcome measure and head injury as a predictor variable. No difference was seen in rate of decline of the ALSFRS-R between patients with head injury (n = 24) and without (n = 76), with mean monthly decline of -0.9 for both groups (p = 0.18). Of 47 ALS autopsy cases (n = 9 with head injury, n = 38 without), no significant differences were seen in the frequency of tau proteinopathy (11% with head injury; 24% without), TDP-43 in the brain (44% with head injury; 45% without), or AD pathology (33% with head injury; 26% without). Independent logistic regression models showed head injury was not a predictor of tau pathology (p = 0.42) or TDP-43 in the brain (p = 0.99). Head injury was not associated with faster disease progression in ALS and did not result in a specific neuropathologic phenotype. The tau pathology described with chronic traumatic encephalopathy was found in ALS autopsy cases both with and without head injury.

Dysregulated mitochondrial Ca2+ and ROS signaling in skeletal muscle of ALS mouse model

The System Usability Scale (SUS) score survey is a widely respected tool for measuring usability. While there are other surveys available such as the User Experience Questionnaire (UEQ) or the Single Ease Question (SEQ), the SUS is amongst the most popular and widely used instrument. SUS provides an easy-to-understand score with benchmarking. Generally, a SUS score is administered directly after a usability test to assess the user experience and the usability of a product, including websites and smartphone apps and more. However, some researchers have used it as a survey as part of a ‘in the wild’ trial which is often completed after the trial or indeed sometime after the subjects interacted with the technology. With this in mind the aim of this research was to see if a participant’s user experience would change if a SUS score was administered at different times after a test to understand if recalling the usability of technology led to temporal bias for the SUS.

The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.

Objective: To explore the impacts of nutritional biomarkers regarding glucose, protein and lipid on amyotrophic lateral sclerosis (ALS) progression and survival in a cohort of Chinese ALS patients. Methods: A total of 191 ALS patients were included in our analysis. Pearson correlation was employed to analyze the relationships between baseline serological and clinical variables. Uni- and multivariate analysis were performed to analyze the influence of nutritional biomarkers on the progression and survival of ALS. A p-value of less than 0.05 was considered to be statistically significant. Results: Hyperglycemia (around 1/6) and hyperlipidemia (1/5-1/3) were common among ALS patients while protein deficiency was not predominant. Serum total cholesterol (TC) (p=0.026) and low-density lipoprotein cholesterol (LDL-C) (p=0.044) was negatively related to baseline ALS functional rating scale-revised (ALSFRS-R) score, while serum PA was positively associated with baseline ALSFRS-R score (p=0.018). Serum levels of TC (p=0.041), apoB (p&lt;0.001), lipoprotein a [Lp (a)] (p=0.002) and free fatty acids (FFA) (p=0.049) were negatively associated with baseline forced vital capacity percentage (FVC%). None of studied biomarkers showed significant relationship with ALS progression or survival time, except for serum level of Lp(a) had a weakly positive correlation to ALS progression rate after backward selection (p=0.048). Conclusion: Serum biomarkers of glucose, lipid or protein might only have a weak relationship with autonomous function and respiratory function status, but have no significant impact on the progression or overall survival of ALS. More studies were needed to provide guidance of nutritional management and diet recommendation for ALS patients.

In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the "astrocytic signature" in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as "producers" and "targets" of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation.