Novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator LT-102: A promising therapeutic agent for treating cognitive impairment associated with schizophrenia.

AIMS: We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action. METHODS: The activity of LT-102 was examined by Ca2+ influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests. RESULTS: LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues. CONCLUSION: We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.

Tracheal extubation under Narcotrend EEG monitoring at different depths of anesthesia after tonsillectomy in children: a prospective randomized controlled study.

Objective: This study aims to investigate whether tracheal extubation at different depths of anesthesia using Narcotrend EEG (NT value) can influence the recovery quality from anesthesia and cognitive function of children who underwent tonsillotomy. Methods: The study enrolled 152 children who underwent tonsillotomy and were anesthetized with endotracheal intubation in our hospital from September 2019 to March 2022. These patients were divided into Group A (conscious group, NT range of 95-100), Group B (light sedation group, NT range of 80-94), and Group C (conventional sedation group, NT range of 65-79). A neonatal pain assessment tool, namely, face, legs, activity, cry, and consolability (FLACC), was used to compare the pain scores of the three groups as the primary end point. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales were used to evaluate the cognitive function of children in the three groups before and after surgery as the secondary end points. Results: Differences were observed in the awakening time and FLACC scores after awakening among the three groups (P < 0.05). Among them, Group A exhibited a significantly shorter awakening time and higher FLACC score after awakening than those in Groups B and C (both P < 0.05). The total incidence of adverse reactions in Group B was significantly lower than that in Groups A and C (P < 0.05). No significant difference was observed in MMSE and MoCA scores before the operation and at 7 days after the operation among the three groups (P > 0.05), but a significant difference was found in MMSE and MoCA scores at 1 day and 3 days after the operation among the three groups (P < 0.05). In addition, MMSE and MoCA scores of the three groups decreased significantly at 1 day and 3 days after the operation than those at 1 day before the operation (P < 0.05). Conclusion: When the NT value of tonsillectomy is between 80 and 94, tracheal catheter removal can effectively improve the recovery quality and postoperative cognitive dysfunction of children.

The Role of Sensory Impairment in Cognitive Health Appraisal: A Study of Older Korean Americans Living in Subsidized Senior Housing.

OBJECTIVES: We examined how the association between cognitive performance and cognitive health appraisal would be moderated by vision and/or hearing impairment. METHODS: Data were collected from 315 older Korean-American residents in subsidized senior housing in Los Angeles (M age = 79.4 years). Linear regression models examined the direct and interactive effects of cognitive performance, vision impairment, and hearing impairment on cognitive health appraisal. RESULTS: Negative appraisal of cognitive health was associated with lower cognitive performance and poorer ratings for vision and hearing. Moreover, we found a significant interaction between cognitive performance and hearing impairment (ß = .13, p < .05), as well as a three-way interaction among cognitive performance, vision impairment, and hearing impairment (ß = .12, p < .05). DISCUSSION: The association between objective and subjective measures of cognition was weakened when hearing was impaired. Such a pattern was further evident when both vision and hearing were impaired.

Efficacy of interventions to improve cognitive function in adults with spinal cord injury: A Systematic Review.

Cognitive impairment is a common complication following spinal cord injury (SCI) and imposes a significant negative impact on adjustment, functional independence, physical and mental health, and quality of life. It is unclear whether interventions for cognitive impairment following SCI are effective. A systematic review of controlled trials was performed to evaluate the effect of interventions on cognitive functions in adults with SCI using search engines: Embase, The Cochrane Library, MEDLINE, Scopus, CINAHL, and Web of Science up to December 2023. Two reviewers independently screened the articles and study findings were synthesized and summarized. The risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Eight moderate-quality studies were found that investigated the effects of physical exercise/activity-based therapy plus cognitive training or intermittent hypoxia, diet modification and dietary supplements, tibial nerve or cortical stimulation, and drug therapy on cognitive function in SCI. Physical exercise/activity-based therapy plus cognitive training showed most promise for improving cognitive functions while drug therapy, diet modification and dietary supplements showed potential for improving cognitive function. However, about half of the participants experienced heightened instability in blood pressure following the administration of midodrine, and one participant reported gastrointestinal side effects after taking omega-3 fatty acids. There was no evidence of improvement in cognitive function for stimulation techniques. The current review highlights the scarcity of research investigating the effectiveness of interventions that target cognitive function after SCI. Furthermore, the effects of these eight studies are uncertain due to concerns about the quality of designs and small sample sizes utilized in the trials, as well as the employment of insensitive neurocognitive tests when applied to adults with SCI. This review highlights a significant gap in knowledge related to SCI cognitive rehabilitation.

Comparison of propofol and desflurane for postoperative neurocognitive function in patients with aneurysmal subarachnoid hemorrhage: A prospective randomized trial.

Background: Following aneurysmal subarachnoid hemorrhage, 40-50% of survivors experience cognitive dysfunction, which affects their quality of life. Anesthetic agents play a pivotal role in aneurysm surgeries. However, substantial evidence regarding their effects on neurocognitive function is lacking. This study evaluated the effects of propofol and desflurane on postoperative neurocognitive function and serum S-100B levels. Methods: One hundred patients were equally randomized to receive either propofol (Group P) or desflurane (Group D). Cognitive function was assessed using the Montreal Cognitive Assessment scale at three different time points: Preoperatively, at the time of discharge, and one month after surgery. Perioperative serum levels of S-100B were also measured. Results: The preoperative mean cognitive score in Group P was 21.64 + 4.46 and in Group D was 21.66 + 4.07 (P = 0.79). At discharge, a significant decrease in cognitive scores was observed compared to preoperative scores (Group P- 20.91 + 3.94, P = 0.03 and Group D-19.28 + 4.22, P = 0.00); however, scores were comparable between the two groups (P = 0.09). One month following surgery, mean cognitive scores were 22.63 + 3.57 in Group P and 20.74 + 3.89 in Group D, and the difference was significant (P = 0.04). Higher memory and orientation scores were observed in Group P than in Group D at one month (P < 0.05) in the subgroup analysis. Both groups had similar serum S-100B levels. Conclusion: The mean cognitive scores one month after surgery improved significantly with propofol compared with desflurane, but without clinical significance. Individual domain analysis demonstrated that orientation and memory scores were better preserved with propofol.

Cognitive behavioural therapy for depression, quality of life, and cognitive function in the post-stroke period: systematic review and meta-analysis.

The post-stroke period is associated with a lot of sequelae, including depression, decreased quality of life, and decline of cognitive function. Apart from the pharmacotherapy, it is also important to find a non-pharmacological treatment to relieve the sequelae. Cognitive behavioural therapy (CBT) might be a potential candidate, which can be clarified by a systematic review and meta-analysis. The eligible criteria of enrolled studies in the systematic review and meta-analysis were the randomised clinical trials (RCTs) using CBT to treat post-stroke depression, or with the focus on quality of life or cognitive function in the post-stroke period. The endpoint scores of depression, quality of life, and cognitive function scales were the targeted outcome for the final meta-analysis in the random effects model. Ten RCTs with 432 post-stroke patients receiving CBT and 385 controls were included. The meta-analysis results showed significant improvements in depression severity and quality of life. However, no significant difference between CBT and control groups was found in cognitive function. In addition, significant heterogeneity was derived from the meta-analysis. According to the meta-analysis results, CBT might be beneficial for relieving depression severity and improving quality of life. However, cognitive function might not be influenced by CBT. Further studies with a more consistent CBT design with greater sample sizes should be warranted to clarify and confirm the treatment effects of CBT for post-stroke depression and quality of life.

Research progress on intestinal microbiota regulating cognitive function through the gut-brain axis.

The intestinal microbiota community is a fundamental component of the human body and plays a significant regulatory role in maintaining overall health and in the management disease states.The intestinal microbiota-gut-brain axis represents a vital connection in the cognitive regulation of the central nervous system by the intestinal microbiota.The impact of intestinal microbiota on cognitive function is hypothesized to manifest through both the nervous system and circulatory system. Imbalances in intestinal microbiota during the perioperative period could potentially contribute to perioperative neurocognitive dysfunction. This article concentrates on a review of existing literature to explore the potential influence of intestinal microbiota on brain and cognitive functions via the nervous and circulatory systems.Additionally, it summarizes recent findings on the impact of perioperative intestinal dysbacteriosis on perioperative neurocognitive dysfunction and suggests novel approaches for prevention and treatment of this condition.

White matter hyperintensities mediate the association between frailty and cognitive impairment in moyamoya disease.

OBJECTIVES: The relationship between cognitive function and frailty in moyamoya disease (MMD) remains unclear, and the underlying mechanism is poorly understood. This study aims to investigate whether white matter hyperintensities (WMHs) mediate the association between frailty and cognitive impairment in MMD. METHODS: Patients with MMD were consecutively enrolled in our study from January 2021 to May 2023. Pre-admission frailty and cognition were assessed using the Clinical Frailty Scale (CFS) and cognitive tests, respectively. Regional deep WMH (DWMH) and periventricular WMH (PWMH) volumes were calculated using the Brain Anatomical Analysis using Diffeomorphic deformation toolbox based on SPM 12 software. Multivariate logistic regression analysis was conducted to evaluate the association between frailty and cognitive function in MMD. Mediation analysis was performed to assess whether WMHs explained the association between frailty and cognition. RESULTS: A total of 85 patients with MMD were enrolled in this study. On the basis of the CFS scores, 24 patients were classified as frail, 38 as pre-frail, and 23 as robust. Significant differences were observed in learning, memory, processing speed, executive functions, and semantic memory among the three groups (p < 0.001). Frailty was independently associated with memory and executive functions (p < 0.05); even after controlling for WMH. Mediation analysis indicated that the associations of frailty with memory and executive functions were partially mediated by WMH, DWMH, and PWMH (p < 0.05). CONCLUSION: Frailty is significantly correlated with a higher risk of cognitive impairment in MMD, even after adjusting for other covariates. WMHs partially mediate the association between frailty and cognitive impairment.

Preface: Special issue: 14th International Conference on Brain Energy Metabolism: Energy substrates and microbiome govern brain bioenergetics and cognitive function with aging.

This Preface introduces the Special Issue entitled, "Energy Substrates and Microbiome Govern Brain Bioenergetics and Cognitive Function with Aging", which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 14th International Conference on Brain Energy Metabolism (ICBEM) held on October 24-27, 2022 in Santa Fe, New Mexico, USA. The conference covered the latest developments in research related to neuronal energetics, emerging roles for glycogen in higher brain functions, the impact of dietary intervention on aging, memory, and Alzheimer's disease, roles of the microbiome in gut-brain signaling, astrocyte-neuron interactions related to cognition and memory, novel roles for mitochondria and their metabolites, and metabolic neuroimaging in aging and neurodegeneration. The special issue contains 25 manuscripts on these topics plus three tributes to outstanding scientists who have made important contributions to brain energy metabolism and participated in numerous ICBEM conferences. In addition, two of the manuscripts describe important directions and the rationale for future research in many thematic areas covered by the conference.

Unlocking Cognitive Potential: Association of Sarcopenia and Mediterranean Diet on Cognitive Function in Community-Dwelling Elderly of the Dalmatian Region.

The aim of this study was to determine the association between muscle strength, adherence to the Mediterranean diet (MeDi) and cognitive function in community-dwelling elderly. General data, data of body composition and anthropometric parameters, clinical and laboratory findings, cognitive test questionnaires (Mini-Mental State Examination-MMSE, Trail Making Test-TMT, Symbol Digit Modalities Test-SDMT), and nutritional assessments (Mini Nutritional Assessment-MNA, Mediterranean Diet Serving Score-MDSS) were obtained for each study participant. Handgrip strength (HS) was used as one of the key parameters for defining probable sarcopenia, among the Short Physical Performance Battery test (SPPB) (for defining physical activity) and the strength, assistance with walking, rising from a chair, climbing stairs, and falls questionnaire (SARC-F). Our cross-sectional study involved 114 participants aged ≥ 60 years, and two-thirds of the participants were female (76.3% vs. 23.7%). Probable sarcopenia was found in 34.7% of them. Using bivariate regression analysis, cognitive deficit among the sarcopenic population was associated with the following groups of collected data: (a) sociodemographic-associated factors-advanced age (OR: 1.07; p = 0.004), single marital status (OR: 3.25; p = 0.03), and low level of education (OR: 0.22; p < 0.003); (b) behavioral-associated factors-duration of institutionalization (OR: 1.05; p = 0.007), performance of heavy physical work (OR: 6.26; p = 0.001), low physical activity (OR: 0.08; p = 0.002), and risk of malnutrition (OR: 3.87; p = 0.005); (c) disease-related factors-loss of appetite (OR: 2.24; p = 0.04), information processing speed (OR: 0.88; p < 0.001), blood pressure systolic/diastolic variables (OR: 0.96/0.96; p = 0.002/0.02), medications (OR: 1.19; p = 0.005), predictive sarcopenia score ≥ 4 (OR: 3.1; p = 0.003), and low muscle strength (OR: 0.92; p = 0.002). Cognitive preservation among the sarcopenic population was associated with married status (OR: 0.23; p = 0.20), a high level of education (OR: 0.18; p = 0.002), smoking (OR: 0.33; p = 0.02), high physical activity (OR: 0.07; p < 0.001), and dietary habits using poultry (OR: 0.12; p = 0.004). The results suggest a significant association between sarcopenia and cognitive function in community-dwelling elderly, highlighting the need for regular nutritional interventions in this special population.

The Positive Association between Melatonin-Containing Food Consumption and Older Adult Life Satisfaction, Psychoemotional State, and Cognitive Function.

The purpose of this study was to test the hypothesis that melatonin-containing food (FMT) consumption is associated with a better sleep schedule and cognitive and psychoemotional state in older adults. A cross-sectional study of 557 (79% females) older adults living in the community with a mean age of 68.9 ± 7.7, ranging from 50 to 90 years, was conducted. The study, conducted in May and September 2023 using a face-to-face interview, collected personal data and assessed FMT intake during the day (FMTday) and for dinner (FMTdinner), life satisfaction, positive and negative affect, depression severity, cognitive functions, and sleep characteristics. Multiple regression and logistic regression analysis, adjusted for co-factors, were used to assess the association between the studied indicators. Multiple regression analysis showed that older adults with higher FMT consumption are more satisfied with life (FMTdinner: ß = 0.107; ∆R2 = 0.011; p = 0.020), have a lower level of depression (FMTday: ß = -0.124; ∆R2 = 0.015; p = 0.003), and higher scores in positive affect (FMTday: ß = 0.169; ∆R2 = 0.016; p = 0.007; FMTdinner: ß = 0.136; ∆R2 = 0.019; p = 0.003). Logistic regression analysis showed that older adults with higher FMT consumption are less likely to have depression (FMTday: OR, 0.614; 95% CI, 0.436-0.864; p = 0.005; FMTdinner: OR, 0.671; 95% CI, 0.476-0.945; p = 0.023), and they perform better on logical thinking tests (FMTday: OR, 2.066; 95% CI, 1.131-2.204; p = 0.013; FMTdinner: OR, 1.887; 95% CI, 1.183-2.138; p = 0.033). A greater life satisfaction as well as a decrease in the cognitive impairment and psychoemotional state of older adults is associated with a higher consumption of melatonin-containing foods.

Hemispheric Lateralization in Older Adults Who Habitually Play Darts: A Cross-Sectional Study Using Functional Near-Infrared Spectroscopy.

Exercise training integrating physical and cognitive activities is gaining attention because of its potential benefits for brain health. This study focuses on exercise training using a dart game called Wellness Darts. Wellness Darts is a sport involving throwing darts and walking to pull them out of the board, memorizing the score, and subtracting this from the total score, thus requiring the simultaneous performance of two tasks: exercise and calculation. This is expected to maintain and improve cognitive function, and whether this continual darts training affects brain function is of great interest. Before conducting the longitudinal study revealing its effect on brain function, we aimed to cross-sectionally confirm the difference in hemispheric lateralization between expert and non-expert players. Functional near-infrared spectroscopy (fNIRS) was used to measure brain activity for three groups: an expert older group who practiced darts continually, a non-expert older control group, and a non-expert younger control group. Their brain activity patterns were quantified by the lateralization index (LI) and compared between groups. The results showed that the younger and the expert older groups had significantly higher LI values than the non-expert older group, and there was no difference between the expert older and the younger groups. Our results suggest that the Wellness Darts game possibly promotes hemispheric lateralization.

Neurobiological and Behavioral Underpinnings of Perinatal Mood and Anxiety Disorders (PMADs): A Selective Narrative Review.

Perinatal mood and anxiety disorders (PMADs) profoundly impact maternal and infant health, affecting women worldwide during pregnancy and postpartum. This review synthesizes current research on the neurobiological effects of PMADs, particularly their influence on brain structure, function, and corresponding cognitive, behavioral, and mental health outcomes in mothers. A literature search across PubMed, PsycINFO, and Google Scholar yielded studies utilizing neuroimaging (MRI, fMRI) and cognitive assessments to explore brain changes in PMADs. The key findings indicate significant neurobiological alterations in PMADs, such as glutamatergic dysfunction, neuronal damage, and altered neural connectivity, particularly in postpartum depression (PPD). Functional MRI studies reveal distinct patterns of brain function alteration, including amygdala non-responsivity in PPD, differing from traditional major depressive disorder (MDD). These neurobiological changes are connected with cognitive impairments and behavioral modifications, impacting maternal caregiving. Understanding these alterations is fundamental for developing effective treatments. The findings emphasize the importance of focusing on maternal mental health, advocating for early detection, and personalized treatment strategies to improve maternal and child outcomes.

Platelet Dynamics in Neurodegenerative Disorders: Investigating the Role of Platelets in Neurological Pathology.

Background: Neurological disorders, particularly those associated with aging, pose significant challenges in early diagnosis and treatment. The identification of specific biomarkers, such as platelets (PLTs), has emerged as a promising strategy for early detection and intervention in neurological health. This systematic review aims to explore the intricate relationship between PLT dynamics and neurological health, focusing on their potential role in cognitive functions and the pathogenesis of cognitive disorders. Methods: Adhering to PRISMA guidelines, a comprehensive search strategy was employed in the PubMed and Scholar databases to identify studies on the role of PLTs in neurological disorders published from 2013 to 2023. The search criteria included studies focusing on PLTs as biomarkers in neurological disorders, their dynamics, and their potential in monitoring disease progression and therapy effectiveness. Results: The systematic review included 104 studies, revealing PLTs as crucial biomarkers in neurocognitive disorders, acting as inflammatory mediators. The findings suggest that PLTs share common features with altered neurons, which could be utilised for monitoring disease progression and evaluating the effectiveness of treatments. PLTs are identified as significant biomarkers for detecting neurological disorders in their early stages and understanding the pathological events leading to neuronal death. Conclusions: The systematic review underscores the critical role of PLTs in neurological disorders, highlighting their potential as biomarkers for the early detection and monitoring of disease progression. However, it also emphasises the need for further research to solidify the use of PLTs in neurological disorders, aiming to enhance early diagnosis and intervention strategies.

Cognitive Effects of Reducing First-Generation Antipsychotic Dose Compared to Switching to Ziprasidone in Long-Stay Patients with Schizophrenia.

Background: Cognitive impairment is a core symptom of schizophrenia and is associated with functional outcomes. Improving cognitive function is an important treatment goal. Studies have reported beneficial cognitive effects of the second-generation antipsychotic (SGA) ziprasidone. Reducing the dose of first-generation antipsychotics (FGA) might also improve cognitive function. This study compared the cognitive effects in long-stay patients who were randomized to groups who underwent FGA dose reduction or switched to ziprasidone. Methods: High-dose FGA was reduced to an equivalent of 5 mg of haloperidol in 10 patients (FGA-DR-condition), and 13 patients switched to ziprasidone 80 mg b.i.d. (ZIPRA condition). Five domains of cognitive function were assessed before dose reduction or switching (T0) and after 1 year (T1). This study was approved by the ethics committee of the Open Ankh (CCMO number 338) and registered at the Netherlands Trial Register (code 5864). Results: Non-significant deterioration was seen in all cognitive domains studied in the FGA-DR condition, whereas there was a non-significant improvement in all cognitive domains in the ZIPRA condition. The most robust difference between conditions, in favor of ziprasidone, was in executive function. Conclusions: In patients with severe chronic schizophrenia, ziprasidone had a non-significant and very modest beneficial effect on cognitive function compared with FGA dose reduction. Larger trials are needed to further investigate this effect.

Association between cognitive function and body composition in older adults: data from NHANES (1999-2002).

Aim: To investigate the association between cognitive function and body composition in older adults. Methods: We collected data on 2080 older adults (>60 years of age) from the National Health and Nutrition Examination Survey (NHANES) for the years 1999-2000 and 2001-2002. Candidate variables included: demographic data (sex, age, race, education level, marital status, poverty-to-income ratio), alcohol consumption, cardiovascular disease, diabetes, osteoporosis, total bone mineral density, and total fat mass. A logistic regression model was established to analyze the association between cognitive function and body composition in older adults. In addition, stratified logics regression analysis was performed by sex and age. Results: Bone mineral density significantly affects cognitive function in older adults (p<0.01). When examining the data according to sex, this correlation is present for women (p < 0.01). For men, though, it is not significant (p = 0.081). Stratified by age, total bone mineral density was significantly correlated with cognitive function in 60-70 and 70-80 years old people, but not in older adults older than 80 years(for 60-70 years old, p = 0.019; for 70-80 years old, p = 0.022). There was no significant correlation between total bone mineral density and cognitive function (p = 0.575). Conclusion: The decrease of total bone mineral density was significantly correlated with cognitive decline in the older adults, especially among women and older people in the 60 to 80 age group. There was no connection between total fat mass, total percent fat, total lean mass, appendicular lean mass, appendicular lean mass /BMI and cognitive function in the older adults.

Evaluation of Event-Related Potentials in Somatic Diseases - Systematic Review.

Many somatic illnesses (e.g. hypertension, diabetes, pulmonary and cardiac diseases, hepatitis C, kidney and heart failure, HIV infection, Sjogren's disease) may impact central nervous system functions resulting in emotional, sensory, cognitive or even personality impairments. Event-related potential (ERP) methodology allows for monitoring neurocognitive processes and thus can provide a valuable window into these cognitive processes that are influenced, or brought about, by somatic disorders. The current review aims to present published studies on the relationships between somatic illness and brain function as assessed with ERP methodology, with the goal to discuss where this field of study is right now and suggest future directions.

Association between cognitive function and skeletal muscle in patients undergoing maintenance hemodialysis.

Background: Patients on hemodialysis have a higher burden of cognitive impairment than individuals of the same age in the general population. Studies have found a link between cognition and skeletal muscle function. However, few studies have investigated these associations and the underlying mechanisms in patients on hemodialysis. Methods: A total of 166 patients on hemodialysis were enrolled in this longitudinal study. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scores. Skeletal muscle indicators were evaluated using Inbody S10. Plasma brain-derived neurotrophic factor (BDNF) concentrations were measured by enzyme-linked immunosorbent assay. The primary outcome was a change in the MoCA scores. A mediation analysis was performed to examine the indirect effect of skeletal muscle on cognitive decline through BDNF. Results: Among the 166 patients, the average age was 49.9 ± 11.2 years. Of these patients with a median follow-up of 1,136 days, 133 participated in the study. We defined MoCA scores decreased by ≥2 points at 3 years from the baseline measurement as cognitive decline (CD). Compared to the cognitively unchanged group, patients with CD had significantly lower fat-free mass, soft lean mass, skeletal muscle mass, and skeletal muscle index (all P<0.05). After adjusting for potential confounders, skeletal muscle indicators were protective predictors of CD. A significant increase in plasma BDNF levels was observed in the CD group. Mediation analysis suggested that BDNF played a mediating role of 20-35% between cognitive impairment and skeletal muscle. Conclusion: Skeletal muscle is a protective predictor of CD in patients undergoing dialysis. BDNF mediates the relationship between cognitive impairment and skeletal muscle function.

Neuroinflammation alters GABAergic neurotransmission in hyperammonemia and hepatic encephalopathy, leading to motor incoordination. Mechanisms and therapeutic implications.

Enhanced GABAergic neurotransmission contributes to impairment of motor coordination and gait and of cognitive function in different pathologies, including hyperammonemia and hepatic encephalopathy. Neuroinflammation is a main contributor to enhancement of GABAergic neurotransmission through increased activation of different pathways. For example, enhanced activation of the TNFα-TNFR1-NF-κB-glutaminase-GAT3 pathway and the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway in cerebellum of hyperammonemic rats enhances GABAergic neurotransmission. This is mediated by mechanisms affecting GABA synthesizing enzymes GAD67 and GAD65, total and extracellular GABA levels, membrane expression of GABAA receptor subunits, of GABA transporters GAT1 and GAT three and of chloride co-transporters. Reducing neuroinflammation reverses these changes, normalizes GABAergic neurotransmission and restores motor coordination. There is an interplay between GABAergic neurotransmission and neuroinflammation, which modulate each other and altogether modulate motor coordination and cognitive function. In this way, neuroinflammation may be also reduced by reducing GABAergic neurotransmission, which may also improve cognitive and motor function in pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission such as hyperammonemia, hepatic encephalopathy or Parkinson's disease. This provides therapeutic targets that may be modulated to improve cognitive and motor function and other alterations such as fatigue in a wide range of pathologies. As a proof of concept it has been shown that antagonists of GABAA receptors such as bicuculline reduces neuroinflammation and improves cognitive and motor function impairment in rat models of hyperammonemia and hepatic encephalopathy. Antagonists of GABAA receptors are not ideal therapeutic tools because they can induce secondary effects. As a more effective treatment to reduce GABAergic neurotransmission new compounds modulating it by other mechanisms are being developed. Golexanolone reduces GABAergic neurotransmission by reducing the potentiation of GABAA receptor activation by neurosteroids such as allopregnanolone. Golexanolone reduces neuroinflammation and GABAergic neurotransmission in animal models of hyperammonemia, hepatic encephalopathy and cholestasis and this is associated with improvement of fatigue, cognitive impairment and motor incoordination. This type of compounds may be useful therapeutic tools to improve cognitive and motor function in different pathologies associated with neuroinflammation and increased GABAergic neurotransmission.

Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability.

O-GlcNAcylation is a protein modification that is critical for vertebrate development, catalysed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense mutations in OGT have recently been shown to segregate with a X-linked syndromic form of intellectual disability, OGT-linked Congenital Disorder of Glycosylation (OGT-CDG). Although OGT-CDG suggests a critical role of O-GlcNAcylation in neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and OGT/OGA levels in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlation in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.