Glycogen accumulation modulates life span in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord. Glial cells, including astrocytes and microglia, have been shown to contribute to neurodegeneration in ALS, and metabolic dysfunction plays an important role in the progression of the disease. Glycogen is a soluble polymer of glucose found at low levels in the central nervous system that plays an important role in memory formation, synaptic plasticity, and the prevention of seizures. However, its accumulation in astrocytes and/or neurons is associated with pathological conditions and aging. Importantly, glycogen accumulation has been reported in the spinal cord of human ALS patients and mouse models. In the present work, using the SOD1G93A mouse model of ALS, we show that glycogen accumulates in the spinal cord and brainstem during symptomatic and end stages of the disease and that the accumulated glycogen is associated with reactive astrocytes. To study the contribution of glycogen to ALS progression, we generated SOD1G93A mice with reduced glycogen synthesis (SOD1G93A GShet mice). SOD1G93A GShet mice had a significantly longer life span than SOD1G93A mice and showed lower levels of the astrocytic pro-inflammatory cytokine Cxcl10, suggesting that the accumulation of glycogen is associated with an inflammatory response. Supporting this, inducing an increase in glycogen synthesis reduced life span in SOD1G93A mice. Altogether, these results suggest that glycogen in reactive astrocytes contributes to neurotoxicity and disease progression in ALS.

e-Health Literacy Scale, Patient Attitudes, Medication Adherence, and Internal Locus of Control.

BACKGROUND: Health literacy is related to a variety of health outcomes, including disease control, health-related quality of life, and risk for death. Few studies have investigated the relation of electronic health literacy (e-health literacy) to outcomes or the mechanism by which they may be related. METHODS: Secondary data were drawn from participants in a larger study on chronic disease self-management who were age 40 years and older, had at least one chronic health condition and a health literacy score of 8th grade or below on the validated short form of the Rapid Estimate of Adult Literacy in Medicine. Participants completed the e-Health Literacy Scale (eHEALS), the Multidimensional Health Locus of Control scale, a modified version of the Attitudes Toward Health Care Providers Scale (ATHCPS), the Wake Forest Physician Trust Scale (WFPTS), and the Gonzalez-Lu adherence questionnaire. Hypothesized relations were evaluated in a bootstrapped path analytic model using the Mplus statistical software. KEY RESULTS: Participants included 334 individuals (mean age: 57.5 years; 173 women and 161 men) with Black, Indigenous, and People of Color accounting for 83.3% of the participants and White individuals making up 16.7% of the participants. Model results showed that after controlling for age, education, gender, and race, the eHEALS score was significantly related to the ATHCPS and WFPTS but not to the Gonzalez-Lu adherence questionnaire (p < .05). The eHEALS score was significantly related to the Multidimensional Health Locus of Control scale. Analysis of indirect effects showed that a portion of the relation between e-health literacy and patient attitude and adherence was mediated by internal locus of control (all p < .05). CONCLUSIONS: In this study, e-health literacy was related to important patient attitude and behavior variables via locus of control. This finding has implications for the importance of improving patients' ability to use the internet to access and effectively use health information. [HLRP: Health Literacy Research and Practice. 2023;7(2):e80-e88.].

Chronic Disease Self-Management of Post-Acute Sequelae of COVID-19 Among Older Adults: A Mixed-Methods Analysis.

Introduction: Approximately 20-30% of individuals who contract acute coronavirus disease (COVID-19) infection develop longer term complications of their initial infection, referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). PASC is characterized by chronic, varying symptomatology. Methods: Using a mixed methods study design, we aimed to gain insight into individuals' experience with PASC, including cognitive issues, fatigue, and sleep disturbances. We explored whether our previously developed application (app), aimed at improving self-management skills among individuals with chronic diseases, is relevant for individuals with PASC and gained information to adapt the app for individuals with PASC. The study included 19 individuals, aged 40 years and older, recruited from our research participant database, Nova Southeastern University clinics, and community locations. We included this age range because older adults are more likely to have comorbid conditions, allowing us to better understand the impact of COVID-19 infection in these individuals. Participants completed seven standardized self-report questionnaires online, and an individual semi-structured interview via videoconferencing. Quantitative data were assessed using descriptive statistics and calculating individuals' scores in relation to norms. Qualitative data were analyzed using a thematic analysis approach. Triangulation of the data was accomplished by calculating correlations between participants' responses on self-report scales and themes found in semi-structured interviews. Results: Themes included disruption of everyday life, diverse physical symptoms, and cognitive problems including brain fog, fatigue, coping, and emotional upset. Quantitative analysis demonstrated that participants experienced high levels of fatigue, negative mood, cognitive problems, and overall reduction in health-related quality of life (HRQOL). Correlation analyses revealed that individual interview responses were related to participants' self-report of symptoms on standard questionnaires. Discussion: Findings indicate that self-report questionnaires may reflect the experience of individuals with PASC and its impact. Additionally, further efforts to expand our prior mobile app are warranted among individuals with PASC.

A mobile app for chronic disease self-management for individuals with low health literacy: A multisite randomized controlled clinical trial.

Objective: The purpose of this study was to evaluate the effects of a mobile app designed to improve chronic disease self-management in older adult patients with low health literacy and who had at least one chronic health condition, and to assess the impact of delivering information at different levels of reading difficulty. Methods: A randomized controlled trial was completed at two sites. Individuals 40 years of age and older screened for low health literacy who had at least one chronic health condition were randomly assigned to a tailored information multimedia app with text at one of three grade levels. Four primary outcomes were assessed: patient activation, chronic disease self-efficacy, health-related quality of life, and medication adherence. Results: All groups showed overall increases in activation, self-efficacy, and health-related quality of life, but no change in medication adherence. No between-group differences were observed. Conclusions: The mobile app was effective in increasing participants' levels of several psychosocial variables, but reading difficulty level was not significantly related to outcomes.Registered at clinicaltrials.gov NCT02922439.

Increasing Surplus Food Redistribution to Improve Food Access Through a Partnership Between Public Health and a Technology-Based Company.

Redistributing surplus food that would otherwise be discarded represents a viable strategy both for increasing food access and for addressing climate change. This study describes a public-private partnership that scaled such an effort in Los Angeles County. Public health worked with a technology-based company to introduce a mobile app that connected various traditional (e.g., food pantries) and non-traditional (e.g., businesses with surplus food, food rescue organizations, community-based organizations that work in low-income communities) organizations with a countywide surplus food redistribution process. In 11 months, 50 food businesses participated, a total of 43,900 pounds of food were recovered, and surplus food was delivered to 34 community sites, serving 28,400 meals. Lessons from the experience suggest that mobile app use was a key component of the redistribution effort, and that diverting food waste while increasing food access, with a priority towards obtaining food of high nutritional value, was both feasible and practical. It has previously been shown that reducing food loss and waste by at least 50% in the food service sector could help reduce energy use and greenhouse gas emissions.

Certification program of Addiction Centres for hepatitis C virus elimination in Spain. HepCelentes Project. / Programa de certificación de Centros de Adicciones para la eliminación del virus de la hepatitis C en España. Proyecto HepCelentes.

Microelimination strategies for the hepatitis C virus (HCV) in vulnerable populations, such as users of Addiction Centres (AC), are key for the elimination of hepatitis C. The aim of the HepCelentes project was to design a certification program for AC from the generation of a guide with the criteria to favour the prevention, diagnosis, control, and treatment of HCV in Spain. The project was structured in 4 phases: normalisation, implementation, certification, and communication. In the first phase, developed between July and December 2020, a Steering Committee was created (formed by representatives of scientific societies, healthcare professionals from AC, primary care centres and hospital units, and patient associations) that, from of an exhaustive bibliographic review, generated by consensus an accreditation guide for AC. The guide consists of 22 criteria (15 mandatory and 7 recommended) structured based on the requirements to be met by AC, justification for the selection, level of action (management, prevention, diagnosis and treatment/follow-up), measurement of the indicator, objective level to be achieved, evidence of compliance, clarifications to improve understanding, and mandatory / recommendation (depending on their relevance to achieve HCV elimination and its feasibility for implementation in real practice). The development of a certification system for the AC, based on consensus and coordination of multidisciplinary teams, is intended to favour the management of hepatitis C and its elimination in AC users, supporting the international, national, and regional elimination strategies.

Las estrategias de microeliminación del virus de la hepatitis C (VHC) en poblaciones vulnerables, como los usuarios de los centros de adicciones (CA), son fundamentales para lograr la eliminación de la hepatitis C. El objetivo del proyecto HepCelentes fue diseñar un programa de certificación para los CA, a partir de la generación de una guía con los criterios para favorecer la prevención, diagnóstico, control y tratamiento del VHC en España. El proyecto se estructuró en 4 fases: normalización, implementación, certificación y comunicación. En la primera fase, desarrollada entre julio y diciembre de 2020, se creó un Comité de Normalización (formado por representantes de sociedades científicas, profesionales sanitarios de CA, centros de atención primaria, unidades hospitalarias, y asociaciones de pacientes) que, a partir de una revisión bibliográfica exhaustiva, generó por consenso una guía de certificación de los CA. La guía consta de 22 criterios (15 obligatorios y 7 recomendados) estructurados en base a la definición del criterio, justificación de su selección, nivel de actuación (gestión, prevención, diagnóstico y tratamiento/seguimiento), fórmula de medición, nivel objetivo a alcanzar, evidencias de su cumplimiento, aclaraciones para mejorar su comprensión y obligatoriedad/recomendación (en función de la relevancia en la eliminación y capacidad de implementación). El desarrollo de un sistema de certificación para los CA, a partir del consenso y la coordinación de equipos multidisciplinares, pretende favorecer el manejo de la hepatitis C y su eliminación en los usuarios de los CA, apoyando las estrategias de eliminación internacionales, nacionales y autonómicas.

Sleep Quality After Intradialytic Oral Nutrition: A New Benefit of This Anabolic Strategy? A Pilot Study.

Background: Since disturbances of appetite and sleep are closely related and both affect metabolic disorders, it would be expected that a renal specific oral nutritional supplement (RS-ONS) that covers the energy the patient does not consume on the HD day, could contribute to improve the nutritional status and body composition, as well as sleep quality. There is still scarce information related to this topic. Aim: To evaluate the effect of the use of intra-dialytic RS-ONS vs. RS-ONS at home on sleep quality, nutritional status, and body composition in patients on HD. Methods: Adult patients < 65 years, with ≥3 months on HD were invited to participate in an open randomized pilot study (ISRCTN 33897). Patients were randomized to a dialysis-specific high-protein supplement provided during the HD session (Intradialytic oral nutrition [ION]) or at home (control), during non-HD days (thrice weekly, for both) 12 weeks. The primary outcome was sleep quality defined by the Pittsburgh Sleep Quality Index (PSQI) score. Nutritional assessment included Malnutrition Inflammation Score (MIS), bioelectrical impedance analysis, anthropometry, 3-day food records, and routine blood chemistries. Results: A total of 23 patients completed the study. Age was median 35 (range 24-48 years), 42% were women. At baseline, the PSQI score was median 4 (range 2-7), and MIS showed a median of 6 (range 5-8); there were no baseline differences between groups. After intervention, both groups improved their MIS scores and similarly when we analyzed the whole cohort (pre- vs. post-intervention P < 0.01). Patients in the ION group improved the overall PSQI score to median 3 (2-5), and assessment of sleep duration and sleep disturbances (pre- vs. post-intervention P < 0.05), with a trend toward an effect difference compared to patients consuming the supplement at home (P for treatment-effect across arms 0.07 for PSQI score and 0.05 for sleep latency). Conclusion: Oral supplementation improved nutritional status in the whole cohort, but only ION improved the PSQI score. More studies are needed to explore the nutritional strategies that influence the relationship between sleep and nutritional status in HD patients.

A motor neuron disease mouse model reveals a non-canonical profile of senescence biomarkers.

To evaluate senescence mechanisms, including senescence-associated secretory phenotype (SASP), in the motor neuron disease model hSOD1-G93A, we quantified the expression of p16 and p21 and senescence-associated ß-galactosidase (SA-ß-gal) in nervous tissue. As SASP markers, we measured the mRNA levels of Il1a, Il6, Ifna and Ifnb. Furthermore, we explored whether an alteration of alternative splicing is associated with senescence by measuring the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR DNA-binding protein (TDP-43; encoded by Tardbp). Transgenic mice showed an atypical senescence profile with high p16 and p21 mRNA and protein in glia, without the canonical increase in SA-ß-gal activity. Consistent with SASP, there was an increase in Il1a and Il6 expression, associated with increased TNF-R and M-CSF protein levels, with females being partially protected. TDP-43 splicing activity was compromised in this model, and the senolytic drug Navitoclax did not alter the disease progression. This lack of effect was reproduced in vitro, in contrast to dasatinib and quercetin, which diminished p16 and p21. Our findings show a non-canonical profile of senescence biomarkers in the model hSOD1-G93A.

Nonalcoholic Fatty Liver Disease and the Gut-Liver Axis: Exploring an Undernutrition Perspective.

Nonalcoholic fatty liver disease (NAFLD) is a chronic condition affecting one quarter of the global population. Although primarily linked to obesity and metabolic syndrome, undernutrition and the altered (dysbiotic) gut microbiome influence NAFLD progression. Both undernutrition and NAFLD prevalence are predicted to considerably increase, but how the undernourished gut microbiome contributes to hepatic pathophysiology remains far less studied. Here, we present undernutrition conditions with fatty liver features, including kwashiorkor and micronutrient deficiency. We then review the gut microbiota-liver axis, highlighting key pathways linked to NAFLD progression within both overnutrition and undernutrition. To conclude, we identify challenges and collaborative possibilities of emerging multiomic research addressing the pathology and treatment of undernourished NAFLD.

Gut microbes shape microglia and cognitive function during malnutrition.

Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target.

Age-Related Changes in Lipidome of Rat Frontal Cortex and Cerebellum Are Partially Reversed by Methionine Restriction Applied in Old Age.

Lipids are closely associated with brain structure and function. However, the potential changes in the lipidome induced by aging remain to be elucidated. In this study, we used chromatographic techniques and a mass spectrometry-based approach to evaluate age-associated changes in the lipidome of the frontal cortex and cerebellum obtained from adult male Wistar rats (8 months), aged male Wistar rats (26 months), and aged male Wistar rats submitted to a methionine restriction diet (MetR)-as an anti-aging intervention-for 8 weeks. The outcomes revealed that only small changes (about 10%) were observed in the lipidome profile in the cerebellum and frontal cortex during aging, and these changes differed, in some cases, between regions. Furthermore, a MetR diet partially reversed the effects of the aging process. Remarkably, the most affected lipid classes were ether-triacylglycerols, diacylglycerols, phosphatidylethanolamine N-methylated, plasmalogens, ceramides, and cholesterol esters. When the fatty acid profile was analyzed, we observed that the frontal cortex is highly preserved during aging and maintained under MetR, whereas in the cerebellum minor changes (increased monounsaturated and decreased polyunsaturated contents) were observed and not reversed by MetR. We conclude that the rat cerebellum and frontal cortex have efficient mechanisms to preserve the lipid profile of their cell membranes throughout their adult lifespan in order to maintain brain structure and function. A part of the small changes that take place during aging can be reversed with a MetR diet applied in old age.

The Emergence of New-Onset Obsessive and Compulsive Disorder in an Adolescent During COVID-19 Pandemic.

The COVID-19 pandemic has had a huge toll on both the physical and mental health of people around the globe. Neuropsychiatric symptoms, as well as long-term sequelae, have been demonstrated in those afflicted with COVID-19. These symptoms range from cognitive, attention deficit, new-onset anxiety, depression, psychosis, seizures, and post-traumatic stress. Prolonged lockdown led to social isolation which negatively affected the mental well-being of many individuals. This particularly caused a relapse of psychiatric symptoms due to stress related to the COVID-19 pandemic. It sparked an increase in hoarding behaviors such as obtaining germicidal and cleaning supplies. In this report, we present a case of an adolescent male presenting with a new onset of obsessive-compulsive disorder with symptoms similar to olfactory hallucinations and olfactory reference syndrome in the setting of the COVID-19 pandemic.

Lipidomic traits of plasma and cerebrospinal fluid in amyotrophic lateral sclerosis correlate with disease progression.

Since amyotrophic lateral sclerosis cases exhibit significant heterogeneity, we aim to investigate the association of lipid composition of plasma and CSF with amyotrophic lateral sclerosis diagnosis, its progression and clinical characteristics. Lipidome analyses would help to stratify patients on a molecular basis. For this reason, we have analysed the lipid composition of paired plasma and CSF samples from amyotrophic lateral sclerosis cases and age-matched non-amyotrophic lateral sclerosis individuals (controls) by comprehensive liquid chromatography coupled to mass spectrometry. The concentrations of neurofilament light chain-an index of neuronal damage-were also quantified in CSF samples and plasma. Amyotrophic lateral sclerosis versus control comparison, in a moderate stringency mode, showed that plasma from cases contains more differential lipids (n = 122 for raw P < 0.05; n = 27 for P < 0.01) than CSF (n = 17 for raw P < 0.05; n = 4 for P < 0.01), with almost no overlapping differential species, mainly characterized by an increased content of triacylglyceride species in plasma and decreased in CSF. Of note, false discovery rate correction indicated that one of the CSF lipids (monoacylglycerol 18:0) had high statistic robustness (false discovery rate-P < 0.01). Plasma lipidomes also varied significantly with the main involvement at onset (bulbar, spinal or respiratory). Notably, faster progression cases showed particular lipidome fingerprints, featured by decreased triacylclycerides and specific phospholipids in plasma, with 11 lipids with false discovery rate-P < 0.1 (n = 56 lipids in plasma for raw P < 0.01). Lipid species associated with progression rate clustered in a relatively low number of metabolic pathways, mainly triacylglyceride metabolism and glycerophospholipid and sphingolipid biosynthesis. A specific triacylglyceride (68:12), correlated with neurofilament content (r = 0.8, P < 0.008). Thus, the present findings suggest that systemic hypermetabolism-potentially sustained by increased triacylglyceride content-and CNS alterations of specific lipid pathways could be associated as modifiers of disease progression. Furthermore, these results confirm biochemical lipid heterogeneity in amyotrophic lateral sclerosis with different presentations and progression, suggesting the use of specific lipid species as potential disease classifiers.

Demographic Pattern and Mortality Risk Factors for Prescription Opioid Overdose Hospitalizations: Results From Nationwide Inpatient Sample Analysis.

Objectives To explore the demographic patterns of hospitalizations related to prescription opioid overdose (POD) and evaluate the mortality risk of association in POD inpatients. Methodology We conducted a cross-sectional study using the Nationwide Inpatient Sample of 184,711 POD inpatients. A binomial logistic regression model was used to evaluate the odds ratio (OR) of association for mortality risk due to comorbidities (substance use disorders (SUD) and medical complications) in POD inpatients. Results POD inpatients were majorly females (54.1%), older adults aged 51-75 years (48.5%), whites (81.5%), and from lower household income quartet (32.8%). The most prevalent comorbid SUD among POD inpatients was alcohol (15.7%), followed by cannabis (5.7%), cocaine (4.2%), and amphetamine (1.8%). Comorbid alcohol use disorders had a minimally increased association with mortality but were not statistically significant (OR = 1.036; P = 0.438). POD in patients with cardiac arrest had the highest risk of mortality (OR = 103.423; P < 0.001), followed by shock (OR = 15.367; P < 0.001), coma (OR = 13.427; P < 0.001), and respiratory failure (OR = 12.051; P < 0.001). Conclusions Our study indicates that the hospitalizations related to POD were more prevalent among females, elders between 51 and 75 years of age, whites, and those in the lower household income quartet. The prevalence of prescription opioid use and the hospitalization related to POD remains a significant public health issue. POD inpatients with medical complications were at a higher risk of mortality than with comorbid SUD.

Psychiatric Comorbidities in Pediatric Inpatients With Human Immunodeficiency Virus Infection and Impact on Hospital Course: Inputs From a Case-Control Inpatient Study.

Objectives In this study, we aimed to delineate psychiatric comorbidities in pediatric inpatients with versus without human immunodeficiency virus (HIV) infection and to measure its impact on the length of stay (LOS) and cost of treatment during hospitalization. Methodology We conducted a case-control study using the Nationwide Inpatient Sample and included 4,920 pediatric inpatients between the ages of six and 18 years who were sub-grouped by a comorbid diagnosis of HIV (N = 2,595) and non-HIV (N = 2,325) and matched for demographics (age, sex, and race) by propensity case-control matching. Logistic regression analyses were used to evaluate the adjusted odds ratio (aOR) of association for psychiatric comorbidities (depression, anxiety, post-traumatic stress disorder, psychosis, and drug abuse) in the HIV-positive compared with the HIV-negative (as reference category) pediatric inpatients. We measured the differences in the LOS and cost using the independent sample t-test. Results We found that the most prevalent psychiatric comorbidities in the HIV-positive group were anxiety (6.9%), drug abuse (6.6%), psychosis (6.4%), and depression (6.2%). The HIV-positive group had a significantly higher likelihood of comorbid psychosis (aOR: 1.82; 95% confidence interval [CI]: 1.38-2.40) and depression (aOR: 1.79; 95% CI: 1.36-2.36). The mean LOS per hospitalization episode was longer for the HIV-positive group (11.1 days vs. 6.0 days; P < 0.001) compared to the HIV-negative pediatric inpatients. Conclusions We found an increased risk of depression by 79% and psychosis by 82% in the HIV-positive pediatric population. These inpatients also had an extended hospitalization stay (by five days), adding to the healthcare economic burden.

Influence of circadian rhythms on sports performance.

Chronobiology is the scientific discipline of study of biological rhythms, a term that has gained ground in the sports world. Recently numerous studies have indicated that the time of day in which sports are practiced influences the achievement of good physical performance. The aim of this review was to study the relationship between circadian rhythms and physical performance, according to the latest published data. In addition, the physiological processes involved in the physical response and the differences according to the type of sport and athletes' characteristics were studied. A bibliographic search was carried out through five databases (Pubmed, Scopus, Researcher Gate, Google Scholar, UOC Library), focusing on articles published in the last ten years and written in English and Spanish. 36 papers met the inclusion criteria. Body temperature is a factor that shows a circadian pattern with a marked peak in the later afternoon, time of the day at which physical performance is at its highest, i.e. speed, agility, distance covered, jumping power. The perception of effort is also higher in the afternoon. Regarding the chronotype, evening types seem to be the most affected to do sports out of their optimal time-of-day. The tendency shows more morning types as age increases. Training sessions should be planned according to the optimal time of day for each athlete. It's essential to take into account individual chronotype. The desynchronization of circadian rhythms can cause a decrease in physical performance.

Nuclear lipidome is altered in amyotrophic lateral sclerosis: A pilot study.

Nucleocytosolic transport, a membrane process, is impaired in motor neurons in amyotrophic lateral sclerosis (ALS). This study analyzes the nuclear lipidome in motor neurons in ALS and examines molecular pathways linked to the major lipid alterations. Nuclei were obtained from the frozen anterior horn of the lumbar spinal cord of ALS patients and age-matched controls. Lipidomic profiles of this subcellular fraction were obtained using liquid chromatography and mass spectrometry. We validated the mechanisms behind presumable lipidomic changes by exploring ALS surrogate models including human motor neurons (derived from ALS lines and controls) subjected to oxidative stress, the hSOD-G93A transgenic mice, and samples from an independent cohort of ALS patients. Among the differential lipid species, we noted 41 potential identities, mostly belonging to phospholipids (particularly ether phospholipids, as plasmalogens), as well as diacylglycerols and triacylglycerides. Decreased expression of alkyldihydroxyacetonephosphate synthase (AGPS)-a critical peroxisomal enzyme in plasmalogen synthesis-is found in motor neuron disease models; this occurs in parallel with an increase in the expression of sterol carrier protein 2 (SCP2) mRNA in ALS and Scp2 levels in G93A transgenic mice. Further, we identified diminished expression of diacylglycerol-related enzymes, such as phospholipase C ßI (PLCßI) and protein kinase CßII (PKCßII), linked to diacylglycerol metabolism. Finally, lipid droplets were recognized in the nuclei, supporting the identification of triacylglycerides as differential lipids. Our results point to the potentially pathogenic role of altered composition of nuclear membrane lipids and lipids in the nucleoplasm in the anterior horn of the spinal cord in ALS. Overall, these data support the usefulness of subcellular lipidomics applied to neurodegenerative diseases.

The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer's Disease Pathology.

Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer's disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress conditions that favor increased mitochondrial molecular damage with early bioenergetic involvement. This alteration of energy metabolism is the starting point for subsequent changes in a multitude of cell mechanisms, leading to neuronal dysfunction and, ultimately, cell death. These events are induced by changes that come with age, creating the substrate for the alteration of several neuronal pathways that will evolve toward neurodegeneration and, consequently, the development of AD pathology. In this context, the present review will focus on description of the biological mechanisms that confer vulnerability specifically to neurons of the entorhinal cortex, the changes induced by the aging process in this brain region, and the alterations at the mitochondrial level as the earliest mechanism for the development of AD pathology. Current findings allow us to propose the existence of an altered allostatic mechanism at the entorhinal cortex whose core is made up of mitochondrial oxidative stress, lipid metabolism, and energy production, and which, in a positive loop, evolves to neurodegeneration, laying the basis for the onset and progression of AD pathology.

The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity.

The nonenzymatic adduction of malondialdehyde (MDA) to the protein amino groups leads to the formation of malondialdehyde-lysine (MDALys). The degree of unsaturation of biological membranes and the intracellular oxidative conditions are the main factors that modulate MDALys formation. The low concentration of this modification in the different cellular components, found in a wide diversity of tissues and animal species, is indicative of the presence of a complex network of cellular protection mechanisms that avoid its cytotoxic effects. In this review, we will focus on the chemistry of this lipoxidation-derived protein modification, the specificity of MDALys formation in proteins, the methodology used for its detection and quantification, the MDA-lipoxidized proteome, the metabolism of MDA-modified proteins, and the detrimental effects of this protein modification. We also propose that MDALys is an indicator of the rate of aging based on findings which demonstrate that (i) MDALys accumulates in tissues with age, (ii) the lower the concentration of MDALys the greater the longevity of the animal species, and (iii) its concentration is attenuated by anti-aging nutritional and pharmacological interventions.

Succination of Protein Thiols in Human Brain Aging.

Human brain evolution toward complexity has been achieved with increasing energy supply as the main adaptation in brain metabolism. Energy metabolism, like other biochemical reactions in aerobic cells, is under enzymatic control and strictly regulated. Nevertheless, physiologically uncontrolled and deleterious reactions take place. It has been proposed that these reactions constitute the basic molecular mechanisms that underlie the maintenance or loss-of-function of neurons and, by extension, cerebral functions during brain aging. In this review article, we focus attention on the role of the nonenzymatic and irreversible adduction of fumarate to the protein thiols, which leads to the formation of S-(2-succino)cysteine (2SC; protein succination) in the human brain. In particular, we first offer a brief approach to the succination reaction, features related to the specificity of protein succination, methods for their detection and quantification, the bases for considering 2SC as a biomarker of mitochondrial stress, the succinated proteome, the cross-regional differences in 2SC content, and changes during brain aging, as well as the potential regulatory significance of fumarate and 2SC. We propose that 2SC defines cross-regional differences of metabolic mitochondrial stress in the human brain and that mitochondrial stress is sustained throughout the healthy adult lifespan in order to preserve neuronal function and survival.