Neuroprotection beyond neurons: integrated biomarker-based and astroglia- or microglia-targeted approaches to combat neurodegenerative diseases

ObjectivesTo critically evaluate the effectiveness of physical therapy interventions in improving global function, quality of life and fatigue in individuals with amyotrophic lateral sclerosis (ALS).DesignSystematic review and meta-analyses.Data sourcesMEDLINE, EMBASE,...

The devastating age-dependent neurodegenerative disorders, including prevalent Alzheimer's (AD) and Parkinson's diseases (PD), as well as rare such as Huntington's chorea (HD) and Amyotrophic Lateral Sclerosis (ALS), affect millions of people worldwide.Their prevalence is projected to increase due to ageing of the population, with a corresponding increase in the associated socioeconomic impact.Currently, there is no disease-modifying therapy for any neurodegenerative disease.Symptomatic treatments are available for some conditions such as PD and HD, but the therapeutic benefits are transient and limited.Although the causative factors and clinical manifestations are distinct for each neurodegenerative disease, their molecular pathogeneses share common underlying factors, such as excessive levels of reactive oxygen species (ROS), largely due to mitochondrial impairment, neuroinflammation, and disturbances in protein homeostasis (proteostasis).This raises the exciting possibility for developing a universal treatment, targeting these common drivers of neurodegeneration.The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) orchestrates a major endogenous defense mechanism against oxidative and xenobiotic stress, and inflammation, and plays a role in the maintenance of mitochondrial function and cellular proteostasis, suggesting potential benefits of therapeutic targeting of Nrf2 to counteract neurodegeneration.Under stress condition(s), Nrf2 activates the transcriptional upregulation of a large network of cytoprotective genes, allowing adaptation and survival [1].The levels (and activity) of Nrf2 are tightly regulated through ubiquitination and proteasomal degradation mediated by several ubiquitin ligase systems, including Kelch-like ECHassociated protein 1 (Keap1)-Cullin3 (Cul3)/Rbx1, β-transducin repeats-containing protein (β-TrCP)-Cul1, and synoviolin (Hrd1) [2].Of these, Keap1 is the best-understood key negative regulator of Nrf2.Keap1 serves as a sensor for electrophiles and oxidants, which chemically modify specific cysteines in Keap1, resulting in conformational changes that protect Nrf2 from Keap1-directed degradation.As a

Objective:To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families.Methods:We conducted a register-based nested case-control study during 1990–2013 in Sweden to assess whether patients with ALS had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 patients with ALS and 36,480 age-, sex-, and county of birth–matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of patients with ALS and their controls.Results:Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio 1.49, 95% confidence interval 1.35–1.66) compared to individuals without these diseases. After diagnosis, patients with ALS had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio 2.90, 95% confidence interval 2.46–3.43) compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson disease, other dementia, Alzheimer disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of patients with ALS had higher risk of neurodegenerative diseases, whereas only children of patients with ALS had higher risk of psychiatric disorders, compared to relatives of the controls.Conclusions:Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to nonmotor symptoms of ALS and severe stress response toward the diagnosis.

The aim of this study was to evaluate the effect of laughter yoga on the quality of life and sleep quality in individuals with fecal ostomies. This was randomized controlled trial. The sample comprised 55 individuals with an ostomy who received care at Ankara University's I˙bni Sina Hospital Stoma Therapy Unit in Ankara, Turkey. Data were collected over a 2-month period (January and February 2020). Participants were allocated into an intervention group (n = 27) who received a yoga therapy intervention and a control group (n = 28) who received no intervention via simple randomization. Demographic and pertinent clinical variables were obtained during a baseline visit in both groups, along with the Pittsburgh Sleep Quality Index (PSQI) and Stoma-Quality of Life (Stoma-QOL) instruments. The intervention group received laughter yoga weekly over a period of 8 weeks. Mean scores on the PSQI and the Stoma-QOL at baseline were compared. Participants in the intervention had a significant decline in mean PSQI scores (6.85 vs 5.48, P = .044) indicating improvement in sleep quality following the intervention. Analysis revealed no significant difference in mean Stoma-QOL scores (P = .077). Control group participants had no significant difference in either mean PSQI or Stoma-QOL scores following data collection at the end of 8 weeks. Laughter yoga had a positive effect on the sleep quality in individuals with fecal ostomies. Further research is recommended to evaluate the effect of the number of laughter yoga sessions on the sleep quality and quality of life in individuals with ostomies.

The current cross-sectional correlational study aimed to determine the relationship of medication adherence with functionality and quality of life in individuals with bipolar disorder (BD). The research was conducted with 141 individuals with BD followed as outpatients. Data were collected using an information form, Morisky Medication Adherence Scale (MMAS), Quality of Life in Bipolar Disorder Scale (QoL.BD), and Bipolar Disorder Functioning Questionnaire (BDFQ). A significant positive correlation was found between participants' MMAS total score and QoL.BD (p < 0.001) and BDFQ (p < 0.05) scores. A significant positive correlation was also found between QoL.BD and BDFQ scores (p < 0.001). Medication compliance positively affects quality of life and social functionality in individuals with BD. Thus, interventions to increase medication adherence are recommended. [Journal of Psychosocial Nursing and Mental Health Services, 63(3), 27-35.].

Anemia is highly prevalent, especially in older individuals. In selected populations, anemia has been reported to be associated with impaired survival and health-related quality of life. However, data on this impact in the general population are rare. Furthermore, discussions on the optimal definition of anemia have not been conclusive. We investigated these issues using survival data, scores from a health-related quality of life questionnaire (RAND-36), and hemoglobin concentration from 138670 subjects, aged 18-93 years, participating in the Lifelines cohort. Anemia was defined according to World Health Organization criteria and was further subclassified in participants over 60 years old. Anemia was present in 5510 (4.0%) of all 138670 subjects and 516 (2.8%) in the 18667 individuals older than 60 years. Anemia had no impact on overall survival and limited impact on health-related quality of life in individuals less than 60 years old. In contrast, in individuals over 60 years old anemia significantly impaired overall survival and health-related quality of life. The lower health-related quality of life was mainly observed in subscales representing physical functioning. Although consensus on the subclassification of anemia is lacking, our data suggest that particularly anemia of chronic inflammation was associated with worse overall survival and decreased health-related quality of life. Multivariate models confirmed that anemia was an independent risk factor for decreased health-related quality of life in older individuals. Finally, women with a hemoglobin concentration between 12.0-13.0 g/dL (considered anemia in men, but not in women) experienced a significantly lower health-related quality of life. This large, prospective, population-based study indicates that anemia is associated with worse overall survival and health-related quality of life in older individuals, but not in younger individuals. The findings of this study challenge the definition of anemia in women over 60 years old, and suggest that the optimal definition of anemia, in the perspective of health-related quality of life, in women over 60 years old should be altered to a hemoglobin concentration below 13.0 g/dL (8.0 mmol/L), which is comparable to that in men.

Systematic review and meta-analysis. The objective was to summarize the effectiveness of Inspiratory Muscle Training (IMT) on the quality of life in individuals with Spinal Cord Injury (SCI). An online systematic literature search was conducted in the following databases: PubMed/MEDLINE, PubMed CENTRAL, EMBASE, ISI Web of Science, SciELO, CINAHL/SPORTDiscus, and PsycINFO. Randomized and non-randomized clinical studies investigating the effectiveness of IMT in quality of life were included in the present study. The results used the mean difference and 95% confidence interval for maximal inspiratory pressure (MIP), forced expiratory volume in 1 s (FEV1), maximal expiratory pressure (MEP), and the standardized mean differences for the quality of life and maximum ventilation volume. The search found 232 papers, and after the screening, four studies met the inclusion criteria and were included in the meta-analytical procedures (n = 150 participants). No changes were demonstrated in the quality of life domains (general health, physical function, mental health, vitality, social function, emotional problem, and pain) after IMT. The IMT provided a considerable effect over the MIP but not on FEV1 and MEP. Conversely, it was not able to provide changes in any of the quality of life domains. None of the included studies evaluated the IMT effects on the expiratory muscle maximal expiratory pressure. Evidence from studies shows that inspiratory muscle training improves the MIP; however, this effect does not seem to translate to any change in the quality of life or respiratory function outcomes in individuals with SCI.

Objective: Little is known about the effects of SARS-CoV-2 coronavirus disease (COVID-19) on quality of life and social participation in individuals with traumatic brain injury. We aimed to compare social participation and health-related quality of life (HRQoL) in a sample of individuals with TBI before and during the second wave of COVID-19 and explored the relationships between the perceived impacts of COVID-19, social participation, and HRQoL.Patients and methods: Eighteen individuals with traumatic brain injury with a mean (standard deviation) age of 47.7 (17.0) years at 48.2 (10.5) months post-injury were administered a questionnaire on overall disability and participation (Mayo-Portland Adaptability Inventory-4th edition; MPAI-4), HRQoL (Quality of Life after Brain Injury Questionnaire; QOLIBRI), and the Coronavirus Impacts Questionnaire before and during the second wave of the COVID-19 pandemic at an interval of 6.4 (SD = 8.2) months. Results: Compared with pre-pandemic levels, individuals with traumatic brain injury reported a statistically significant decrease in the QOLI-BRI total score and its emotional subscale (with medium to large effect sizes), but without statistically significant differences in MPAI-4 scores. Increased difficulties with access to resources during COVID-19 were associated with increased adjustment problems on the MPAI-4, and with daily life and autonomy difficulties, emotional issues, and lower physical functioning on the QOLIBRI. Conclusion: The relationships identified in this exploratory correlational study suggest that COVID-19 had a negative impact on quality of life in individuals with traumatic brain injury, but not specifically on their social participation. LAY ABSTRACTLittle is known about the effects of SARS-CoV-2 coronavirus disease (COVID-19) on the lives of individuals with traumatic brain injury. This study compared social participation and health-related quality of life in individuals with TBI before and during the second wave of COVID-19 and explored relationships between the perceived impacts of COVID-19, social participation, and health-related quality of life, but not specifically on social participation in individuals with traumatic brain injury. Also, increased difficulties with access to resources during COVID-19 were associated with increased adjustment problems, daily life and autonomy difficulties, emotional issues, and lower physical functioning.

A Long Shot? Could neurodegenerative disease be caused by a cyanobacterial toxin?

Background:Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.Objective:We examined the potential association between long-term exposure to particulate matter in aerodynamic diameter [fine particulate matter ()] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.Methods:We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000–2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual concentrations estimated by a prediction model at a resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y exposure. We allowed for nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders.Results:We found a positive nonlinear association that plateaued above (, 95% CI: 1.04, 1.14 for a increase from 8.1 to ). We also found a linear positive association (, 95% CI: 1.01, 1.09 per increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.Conclusion:Our findings suggest that annual increase in county-level concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual concentration in our study was , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425

Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause approximately 20% of familial cases of amyotrophic lateral sclerosis (fALS). Accumulating evidence indicates that a gain of toxic function of mutant SOD1 proteins is the cause of the disease. It has also been shown that the ubiquitin-proteasome pathway plays a role in the clearance and toxicity of mutant SOD1. In this study, we investigated the degradation pathways of wild-type and mutant SOD1 in neuronal and nonneuronal cells. We provide here the first evidence that wild-type and mutant SOD1 are degraded by macroautophagy as well as by the proteasome. Based on experiments with inhibitors of these degradation pathways, the contribution of macroautophagy to mutant SOD1 clearance is comparable with that of the proteasome pathway. Using assays that measure cell viability and cell death, we observed that under conditions where expression of mutant SOD1 alone does not induce toxicity, macroautophagy inhibition induced mutant SOD1-mediated cell death, indicating that macroautophagy reduces the toxicity of mutant SOD1 proteins. We therefore propose that both macroautophagy and the proteasome are important for the reduction of mutant SOD1-mediated neurotoxicity in fALS. Inhibition of macroautophagy also increased SOD1 levels in detergent-soluble and -insoluble fractions, suggesting that both detergent-soluble and -insoluble SOD1 are degraded by macroautophagy. These findings may provide further insights into the mechanisms of pathogenesis of fALS.

With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.

EDITORIAL article Front. Neurosci., 06 January 2016Sec. Neurodegeneration Volume 9 - 2015 | https://doi.org/10.3389/fnins.2015.00489

A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress.

IntroductionAssistive technologies (ATs) offer significant potential to improve the quality of life for individuals with Amyotrophic Lateral Sclerosis (ALS). This study explores the concept of integrated user value (IUV), focusing on five key aspects: quality, user experience, cost-effectiveness, safety, and accessibility. Understanding IUV is crucial for enhancing the development and deployment of ATs in ALS disease management.MethodsA systematic search approach was utilized to collect data from Facebook ALS support groups, comprising posts from individuals with ALS and their caregivers. Using a predefined set of keywords, 416 posts were analyzed. The posts were categorized based on the five aspects of IUV, and an in-depth content analysis was conducted to explore patterns, challenges, and experiences associated with AT usage.ResultsThe analysis revealed significant challenges across all aspects of IUV. Quality and user experience were interlinked, with users frequently citing inadequate designs and unmet customization needs. Cost-effectiveness was a key concern, with high costs and limited insurance coverage contributing to financial strain. Accessibility issues, including delays in acquiring devices and insufficient public facilities, further highlighted systemic challenges. Safety concerns emphasized the need for personalized and intuitive AT designs.DiscussionThe findings underscore the importance of a holistic approach to AT development, integrating all five aspects of IUV. Recommendations include enhancing product quality, ensuring affordability, prioritizing user-centered design, and addressing accessibility gaps. Collaboration between AT designers, healthcare providers, and policymakers is essential to optimize AT value and improve the quality of life for individuals with ALS and their caregivers.