The use of peripheral nerve block decrease incidence of postoperative cognitive dysfunction following orthopedic surgery: A systematic review and meta-analysis.

BACKGROUND: Postoperative neurocognitive disorders (PNDs) frequently occur following orthopedic surgery and are closely associated with adverse prognosis. PNDs are an emerging concept that includes both postoperative cognitive dysfunction (POCD) and postoperative delirium (POD). The prevention of combined use of peripheral nerve block (PNB) and general anesthesia (GA) on POCD and/or POD incidence following orthopedic surgery remains unknown. We aimed to investigate the effect of this combined anesthesia method on POCD/POD incidence after orthopedic surgery, compared with GA. METHODS: The databases of PubMed, Web of Science, Embase via Ovid, and the Cochrane Central Register of Controlled Trials were searched for all available randomized controlled trials (RCTs). The incidence of POD/POCD was the primary outcome. Continuous and dichotomous outcomes are represented as standardized mean differences [SMD, 95% confidence interval (CI)] and risk ratios [RR, 95%CI], respectively. RESULTS: Meta-analysis of twelve RCTs with a total of 1488 patients revealed that compared with GA, PNB plus GA decreased the incidence of POCD (RR: 0.58, 95%CI: 0.35 to 0.95, P = 0.03, I2 = 0%), while the incidence of POD had no significant difference (RR: 0.87, 95%CI: 0.54 to 1.40, P = 0.57, I2 = 67%). Compared with GA alone, a significant decrease of intraoperative and postoperative opioid consumption (SMD: -1.54, 95%CI: -2.26 to -0.82, P < 0.0001, I2 = 89%; SMD: -7.00, 95%CI: -9.89 to -4.11, P < 0.00001, I2 = 99%) and postoperative nausea and vomiting incidence (RR: 0.16, 95%CI: 0.06 to 0.44, P = 0.0004, I2 = 0%) was found with PNB plus GA. CONCLUSIONS: The combined use of PNB and GA decreases the incidence of POCD but not POD following orthopedic surgery. TRIAL REGISTRATION: The protocol of this study was registered with PROSPERO (Registration Number: CRD42022366454).

Postoperative Delirium and Neurocognitive Disorders: A Comprehensive Review of Pathophysiology, Risk Factors, and Management Strategies.

Postoperative delirium (POD) and neurocognitive disorders (NCDs) are common and serious complications that can occur after surgery, particularly in older adults and those with preexisting cognitive impairments. These conditions are associated with significant morbidity, increased healthcare costs, and reduced quality of life. Understanding the underlying mechanisms, risk factors, and effective management strategies for POD and NCDs is critical for improving patient outcomes and reducing the burden on healthcare systems. This comprehensive review aims to synthesize current knowledge on the pathophysiology, risk factors, and management strategies for POD and NCDs. It explores the neurobiological and molecular mechanisms contributing to these conditions, identifies the patient-related, surgical, and environmental factors that increase risk, and evaluates pharmacological and non-pharmacological approaches to prevention and treatment. A thorough literature review was conducted using recent studies, clinical guidelines, and expert consensus to provide a detailed overview of the pathophysiology, risk factors, clinical presentation, prevention, and management of POD and NCDs. The pathophysiology of POD and NCDs involves complex interactions between neuroinflammatory processes, neurotransmitter imbalances, and brain network disruptions. Risk factors include advanced age, preexisting cognitive impairment, type and duration of surgery, and perioperative complications. Management strategies emphasize a multidisciplinary approach, incorporating preoperative optimization, careful intraoperative management, and postoperative interventions. Pharmacological treatments, such as antipsychotics, and non-pharmacological approaches, including environmental modifications and cognitive rehabilitation, play crucial roles in management. Postoperative delirium and NCDs are multifactorial conditions with significant impacts on surgical outcomes. Effective management requires a comprehensive understanding of their pathophysiology and risk factors and the implementation of targeted prevention and treatment strategies. Future research should focus on personalized approaches to prevention and treatment, further elucidation of mechanisms, and developing predictive models to enhance care for patients at risk of these neurocognitive complications.

No substantial neurocognitive impact of COVID-19 across ages and disease severity: a multicenter biomarker study of SARS-CoV-2 positive and negative adult and pediatric patients with acute respiratory tract infections.

BACKGROUND: Compared to intensive care unit patients with SARS-CoV-2 negative acute respiratory tract infections, patients with SARS-CoV-2 are supposed to develop more frequently and more severely neurologic sequelae. Delirium and subsequent neurocognitive deficits (NCD) have implications for patients' morbidity and mortality. However, the extent of brain injury during acute COVID-19 and subsequent NCD still remain largely unexplored. Body-fluid biomarkers may offer valuable insights into the quantification of acute delirium, brain injury and may help to predict subsequent NCD following COVID-19. METHODS: In a multicenter, observational case-control study, conducted across four German University Hospitals, hospitalized adult and pediatric patients with an acute COVID-19 and SARS-CoV-2 negative controls presenting with acute respiratory tract infections were included. Study procedures comprised the assessment of pre-existing neurocognitive function, daily screening for delirium, neurological examination and blood sampling. Fourteen biomarkers indicative of neuroaxonal, glial, neurovascular injury and inflammation were analyzed. Neurocognitive functions were re-evaluated after three months. RESULTS: We enrolled 118 participants (90 adults, 28 children). The incidence of delirium [85 out of 90 patients (94.4%) were assessable for delirium) was comparable between patients with COVID-19 [16 out of 61 patients (26.2%)] and SARS-CoV-2 negative controls [8 out of 24 patients (33.3%); p > 0.05] across adults and children. No differences in outcomes as measured by the modified Rankin Scale, the Short-Blessed Test, the Informant Questionnaire on Cognitive Decline in the Elderly, and the pediatrics cerebral performance category scale were observed after three months. Levels of body-fluid biomarkers were generally elevated in both adult and pediatric cohorts, without significant differences between SARS-CoV-2 negative controls and COVID-19. In COVID-19 patients experiencing delirium, levels of GFAP and MMP-9 were significantly higher compared to those without delirium. CONCLUSIONS: Delirium and subsequent NCD are not more frequent in COVID-19 as compared to SARS-CoV-2 negative patients with acute respiratory tract infections. Consistently, biomarker levels of brain injury indicated no differences between COVID-19 cases and SARS-CoV-2 negative controls. Our data suggest that delirium in COVID-19 does not distinctly trigger substantial and persistent subsequent NCD compared to patients with other acute respiratory tract infections. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04359914; date of registration 24-APR 2020.

Inhibitory control and working memory predict rhythm production abilities in patients with neurocognitive deficits.

Deficits in rhythm perception and production have been reported in a variety of psychiatric, neurodevelopmental and neurologic disorders. Since correlations between rhythmic abilities and cognitive functions have been demonstrated in neurotypical individuals, we here investigate whether and how rhythmic abilities are associated with cognitive functions in 35 participants with neurocognitive deficits due to acquired brain lesions. We systematically assessed a diverse set of rhythm perception and production abilities including time and beat perception and finger-tapping tasks. Neuropsychological tests were applied to assess separable cognitive functions. Using multiple regression analyses we show that lower variability in aligning movements to a pacing sequence was predicted by better inhibitory control and better working memory performance. Working memory performance also predicted lower variability of rhythmic movements in the absence of an external pacing sequence and better anticipatory timing to sequences with gradual tempo changes. Importantly, these predictors remained significant for all regression models when controlling for other cognitive variables (i.e., cognitive flexibility, information processing speed, and verbal learning ability) and potential confounders (i.e., age, symptom strength of depression, manual dexterity, duration of illness, severity of cognitive impairment, and musical experience). Thus, all rhythm production abilities were significantly predicted by measures of executive functions. In contrast, rhythm perception abilities (time perception / beat perception) were not predicted by executive functions in this study. Our results, enhancing the understanding of cognitive underpinnings of rhythmic abilities in individuals with neurocognitive deficits, may be a first mandatory step to further potential therapeutic implications of rhythm-based interventions in neuropsychological rehabilitation.

How can patients shape digital medicine? A rapid review of patient and public involvement and engagement in the development of digital health technologies for neurological conditions.

INTRODUCTION: Patient and Public Involvement and Engagement (PPIE) involves working 'with' or 'by' patients and the public, rather than 'to,' 'about,' or 'for' them, and is integral to neurological and digital health research. This rapid review examined PPIE integration in the development and implementation of digital health technologies for neurological conditions. METHODS: Key terms were input into six databases. Included articles were qualitative studies or PPIE activities involving patient perspectives in shaping digital health technologies for neurological conditions. Bias was evaluated using the NICE qualitative checklist, with reporting following PRISMA guidelines. RESULTS: 2,140 articles were identified, with 28 included. Of these, 25 were qualitative studies, and only three were focused PPIE activities. Patient involvement was mostly limited to one-off consultations during development.There was little evidence of PPIE during implementation, and minimal reporting on its impact. CONCLUSIONS: PPIE has been inconsistently reported in this research area, highlighting the need for more guidance and best-practice examples This review used a UK-based definition of PPIE, which may have excluded relevant activities from other countries. Future reviews should broaden terminology to capture PPIE integration globally.

Reliability of the assessment of the clinical dementia rating scale from the analysis of medical records in comparison with the reference method.

BACKGROUND: The Clinical Dementia Rating (CDR) scale allows to detect the presence of dementia and to assess its severity, however its evaluation requires a significant time (45 min). We evaluated the agreement between two methods of collection of the CDR: face-to-face interview or based on the information available in the patient's medical record. METHODS: The CLIMER study was conducted among patients attending a memory center. The CDR scale was evaluated during face-to-face interviews between neuropsychologists and patients and their caregivers and based on blind analysis of the information of the patients' medical record by neuropsychologists. The agreement of the CDR sum of boxes (CDR-SB), the 5-point scale CDR and the different domains of the CDR evaluated between the different methods was measured using intraclass correlation (ICC) coefficient, Bland and Altman method, and linearly weighted Kappa. RESULTS: The study included 139 patients (means ± SD age 80.1 ± 6, 58.3% women, 71.9% with dementia). The ICC for the CDR-SB score assessed by face-to-face and with all the information available in the patient's medical record was 0.95 (95% CI: 0.93-0.97). The mean difference between the CDR-SB score assessed by face-to-face and with the medical record was 0.098 ± 1.036, and 92.4% of the patients lay within the 95% limits of agreement. The ICC for the 5-point scale CDR assessed by face-to-face and with the patient's medical record was 0.92 (95% CI: 0.88-0.95) when all the available information of the patient's medical record was used. The linear weighted Kappa coefficients was 0.79 (95% CI: 0.68-0.91) for the 5-point scale CDR comparison between the two evaluation methods. The analysis by domain of the CDR showed ICC ranging from 0.65 to 0.91 depending of the domains and the methods of evaluation. CONCLUSION: This study showed an excellent level of agreement of the evaluation of the CDR- SB and the 5-point scale CDR when using all the information of the patient's medical record compared to the face-to-face interview. TRIAL REGISTRATION: https//clinicaltrials.gov/ct2/show/NCT04763941 Registration Date 02/17/2021.

The protective effects of apelin-13 in HIV-1 tat- induced macrophage infiltration and BBB impairment.

Impairment of the blood - brain barrier (BBB) and subsequent inflammatory responses contribute to the development of human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND). Apelin-13, the most abundant member of the apelin family, acts as the ligand of the angiotensin receptor-like 1 (APJ). However, its pharmacological function in HAND and its underlying mechanism are unknown. In the current study, we report that the presence of HIV-1 Tat reduced the levels of Apelin-13 and APJ in the cortex tissue of mice. Importantly, Apelin-13 preserved BBB integrity against HIV-1 Tat in mice by increasing the expression of the tight junction protein zonula occludens-1 (ZO-1) and occludin. Interestingly, increased macrophage infiltration, indicated by elevated CD68-positive staining was observed in the cortex after stimulation with HIV-1, which was mitigated by the administration of Apelin-13. Correspondingly, Apelin-13 reduced the expression of monocyte chemoattractant protein-1; (MCP-1). An in vitro two-chamber and two-cell trans-well assay demonstrated that HIV-1 Tat challenge significantly promoted macrophage migration, which was notably attenuated by the introduction of Apelin-13. Accordingly, treatment with Apelin-13 restored the HIV-1 Tat-induced reduction of occludin and ZO-1, while preventing the upregulation of MCP-1 in human brain microvascular endothelial cells (HBMVECs). Our results suggest that Apelin-13 may reduce macrophage infiltration into brain tissues and mitigate BBB dysfunction in patients with HAND.

Differential Social Cognitive Performance in Older Adults With Mild Cognitive Impairment and Dementia.

OBJECTIVE: To study general and subdomain performance in measures of social cognition in individuals with mild cognitive impairment (MCI), and dementia, and to explore associations between social cognitive and neuropsychological subdomains. DESIGN: Cross-sectional study of participants from the Sydney Memory and Ageing Study (MAS). SETTING: Current data was collected in 2016-2018. PARTICIPANTS: Community-dwelling older adults (n=321) aged 80 years and above, with no history of neurological or psychiatric conditions. Participants had dementia, MCI, or no cognitive impairment (NCI). MEASURES: Social cognition was indexed using the Reading the Mind in the Eyes Test (RMET), the Interpersonal Reactivity Index - Perspective Taking (IRI-PT) and Empathic Concern (IRI-EC) subscales, and the Emotion Recognition Task (ERT). These subdomain scores were used to make a composite social cognition score. Apathy was measured via the Apathy Evaluation Scale (AES). Neurocognitive function was indexed using the Addenbrooke Cognitive Examination v3 (ACE-3). RESULTS: Dementia was associated with poorer overall social cognitive composite performance. MCI and dementia participants performed poorer on RMET and recognition of anger, disgust and happiness on ERT. RMET and ERT disgust remained significant after controlling for relevant covariates. Dementia participants performed poorer than MCI and NCI on the IRI-PT, IRI-EC, and AES. AES remained significant after regression. RMET was correlated with ACE-3 Fluency and/or Language in all study groups. CONCLUSIONS: MCI is associated with poorer scores in specific social cognitive assessments. Dementia is somewhat associated with poorer scores in informant-rated social cognition scales, though this is no longer significant after accounting for apathy.

Cannabidiol, a plant-derived compound, is an emerging strategy for treating cognitive impairments: comprehensive review of randomized trials.

Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials. Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables. Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer's disease. Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders.

Knowledge, attitudes, and practices regarding perioperative neurocognitive disorders among anesthesia practitioners.

Objectives: This study aimed to investigate the knowledge, attitudes, and practices (KAP) among anesthesia practitioners concerning perioperative neurocognitive disorders (PND). Methods: This cross-sectional study enrolled anesthesia practitioners from 18 hospitals in China using s self-administered questionnaire between July and September 2023. Results: A total of 200 (98.04 %) valid questionnaire were enrolled, the responders of which aged 36.56 ± 8.24 years, including 130 (65 %) females. The mean KAP scores were 12.28 ± 3.78 (possible range: 0 20),29.22 ± 3.28 (possible range: 8-40), and 29.32 ± 4.30 (possible range: 8-40), respectively. The path analysis demonstrated that number of daily surgical cases (ß = 0.82, p = 0.018), education (ß = 1.49, p < 0.001), and participation in a related research project (ß = 1.32, p = 0.003) had direct effects on knowledge. Working in teaching hospital has direct effect on attitude (ß = 1.82, p = 0.027). Furthermore, knowledge (ß = 0.29, p < 0.001) and attitude (ß = 0.20, p = 0.026) also have direct effects on practice. Conclusions: Anesthesia practitioners had inadequate knowledge, positive attitude, and proactive practice towards PND. Number of daily surgical cases, education, participation in a related research project, and working in teaching hospital might have effects on their KAP.

Curcumin and Cognitive Function: A Systematic Review of the Effects of Curcumin on Adults With and Without Neurocognitive Disorders.

This systematic review investigates the effect of curcumin on neurocognitive exams and inflammatory serum biomarkers in adults 18 years and older. We search PubMed, Science Direct, Google Scholar, Cochrane Library, and Multidisciplinary Digital Publishing Institute. Modeling the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), we screened 1,284 studies with the keywords "neurocognitive disorders," "dementia," "cognitive health," "serum biomarkers," and "curcumin." We use the revised Cochrane Risk-of-Bias tool (RoB2) and the Newcastle-Ottawa Scale to select 12 open-access full-text articles published within 20 years. We include clinical trials, randomized controlled trials (RCTs), cohort studies, and human studies, excluding nonhumans, other design types, and schizophrenia. Despite gastrointestinal side effects, studies found curcumin significantly improves working memory in the following adult groups: non-demented, metabolically impaired, cognitively impaired, mood impaired, and chemotherapy impaired. Study limitations include variable population characteristics and few trials employing intention-to-treat analysis, emphasizing the need for shared clinical decision-making before curcumin therapy.

The Impact of Aging on HIV-1-related Neurocognitive Impairment.

Depending on the population studied, HIV-1-related neurocognitive impairment is estimated to impact up to half the population of people living with HIV (PLWH) despite the availability of combination antiretroviral therapy (cART). Various factors contribute to this neurocognitive impairment, which complicates our understanding of the molecular mechanisms involved. Biological aging has been implicated as one factor possibly impacting the development and progression of HIV-1-related neurocognitive impairment. This is increasingly important as the life expectancy of PLWH with virologic suppression on cART is currently projected to be similar to that of individuals not living with HIV. Based on our increasing understanding of the biological aging process on a cellular level, we aim to dissect possible interactions of aging- and HIV-1 infection-induced effects and their role in neurocognitive decline. Thus, we begin by providing a brief overview of the clinical aspects of HIV-1-related neurocognitive impairment and review the accumulating evidence implicating aging in its development (Part I). We then discuss potential interactions between aging-associated pathways and HIV-1-induced effects at the molecular level (Part II).

Effect of video-based interventions on emergence delirium in pediatric patients: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Emergence delirium is frequently observed in pediatric patients. With advancements in video-based interventions, such as cartoons, video games, and virtual reality, these modalities may contribute to a reduced incidence of emergency delirium among children. However, robust evidence supporting their efficacy remains necessary. METHODS: The authors conducted a systematic search across multiple databases, including Embase, MEDLINE, and Cochrane Library, to identify all randomized controlled trials comparing video-based interventions with control treatments in pediatric emergence delirium. Data were aggregated and analyzed using Review Manager 5.4 to evaluate the effectiveness of video-based interventions. RESULTS: The analysis included eight randomized controlled trials comprising 872 children. The intervention group showed a trend toward lower Pediatric Anesthesia Emergence Delirium scores (p = 0.10) and fewer emergence delirium events (p = 0.52). Seven studies demonstrated that video-based interventions significantly reduced preoperative anxiety, as indicated by decreased scores on the modified Yale Pre-operative Anxiety Scale (p < 0.00001). Anesthesia duration did not significantly differ between the intervention and control groups (p = 0.16). Notably, subgroup analyses revealed a significant reduction in Pediatric Anesthesia Emergence Delirium scores among children under seven years of age (p = 0.001). CONCLUSIONS: Video-based interventions were linked to lower Pediatric Anesthesia Emergence Delirium scores and a decreased incidence of emergence delirium events. However, these results did not reach statistical significance across the broader sample. Notably, in children under seven, these interventions significantly reduced the scores. LEVEL OF EVIDENCE: III.

HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction.

Objectives: Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one's risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction. Methods: Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression. Results: Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression. Conclusion: Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.

ClassIIb histone deacetylase participates in perioperative neurocognitive disorders in elderly mice via HSP90/GR signaling pathway.

OBJECTIVE: Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether Histone Deacetylase 6 (HDAC6) was involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of heat shock protein (HSP90) and related protein functions and quantities. METHODS: C57BL/6 J male mice were randomly divided into six groups: control naive (group Control), anesthesia (group Anesthesia), splenectomy surgery (group Surgery), splenectomy surgery plus dissolvent (group Vehicles), splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and splenectomy surgery plus the inhibitor RU-486(group Mifepristone). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out the following day. Cognitive function was assessed on the 1st, 3rd and 7th days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for Western blots and ELISA assays. RESULTS: Mice with the splenectomy surgery displayed the activation of the hypothalamic-pituitary-adrenal axis (HPA-axis), marked an increase in adrenocorticotropic hormone (ACTH), glucocorticoid, mineralocorticoid at the molecular level and impaired spatial memory in the MWM test. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in glucocorticoid receptor (GR)-HSP90 association, and an increase in GR phosphorylation and translocation. HDAC6 was increased after the surgical treated. Using two specific inhibitors, HDAC6 inhibitor Ricolinostat (ACY-1215) and GR inhibitor Mifepristone (RU-486), can partially mitigate the effects caused by surgical operation. CONCLUSIONS: Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery.

DigiDOP: A framework for applying digital technology to the Differential Outcomes Procedure (DOP) for cognitive interventions in persons with neurocognitive disorders.

We present a framework -Digi-DOP- that includes a series of evidence-based recommendations to design and apply cognitive interventions for people with Neurocognitive Disorders (NCDs) using a relatively new approach, the Differential Outcomes Procedure (DOP). To do so, we critically review the substantial experimental research conducted with relevant clinical and non-clinical populations, and the theoretical underpinnings of this procedure. We further discuss how existing digital technologies that have been used for cognitive interventions could be applied to overcome some of the limitations of DOP-based interventions and further enhance DOP benefits. Specifically, we present three digital DOP developments that are currently being designed, investigated and/or tested. Finally, we discuss constraints, ethical and legal considerations that need to be taken into account to ensure that the use of technology in DOP-based interventions proposed here does not widen disparities and inequalities. We hope that this framework will inform and guide digital health leaders and developers, researchers and healthcare professionals to design and apply DOP-based interventions for people with NCDs.

The PGC-1α/ERRα/ULK1 pathway contributes to Perioperative neurocognitive disorders by inducing mitochondrial dysfunction and activating NLRP3 inflammasome in aged mice.

Perioperative neurocognitive disorders (PND) are intractable, indistinct, and considerably diminish the postoperative quality of life of patients. It has been proved that Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was involved in neurodegenerative diseases by regulating mitochondrial biogenesis. The underlying mechanisms of PGC-1α and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in PND are not well understood. In this study, we constructed a model of laparotomy in aged mice, and then examined the cognition changes with novel object recognition tests and fear condition tests. The protein levels of PGC-1α and NLRP3 in the hippocampus were detect after surgery. Our results showed that NLRP3 and downstream PI3K/AKT pathway expressions were augmented in the hippocampus after surgery, whereas, the expressions of PGC-1α/estrogen-related receptor α (ERRα)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway were diminished after surgery. In addition, we found that NLRP3 was mainly co-localized with neurons in the hippocampus, and synaptic-related proteins were reduced after surgery. At the same time, transmission electron microscopy (TEM) showed that mitochondria were impaired after surgery. Pharmacological treatment of MCC950, a selective NLRP3 inhibitor, effectively alleviated PND. Activation of PGC-1α with ZLN005 significantly ameliorated PND by enhancing the PGC-1α/ERRα/ULK1 signaling pathway, and further suppressing NLRP3 activation. As a result, we conclude that suppression of the PGC-1α/ERRα/ULK1 signaling pathway is the primary mechanism of PND which caused mitochondrial dysfunction, and activated NLRP3 inflammasome and downstream PI3K/AKT pathway, eventually improved cognitive dysfunction.

Health literacy is associated with cognition and everyday functioning in a consecutive clinical series of people with epilepsy in a surgical setting.

OBJECTIVE: Low health literacy is common among people with epilepsy (PWE) and may play an important role in disease management and outcomes. The current study evaluated whether health literacy is related to cognition, health, and everyday functioning in PWE. METHODS: This cross-sectional, correlational study included 25 demographically comparable healthy adults retrospectively matched to a consecutive series of 89 PWE presenting for neuropsychological evaluation in a surgical setting and who completed the Newest Vital Sign and Brief Health Literacy Screener. The PWE also completed a comprehensive neuropsychological battery and measures of quality of life and everyday functioning. RESULTS: PWE had significantly lower health literacy as compared to healthy adults (ps < 0.05) at a medium-to-large effect size. In analyses covarying for education and oral word reading literacy in the PWE sample, lower health literacy was independently associated with bilateral seizure onsets, greater antiseizure medication burden, poorer performance on measures of memory and information processing speed, and difficulties with self-care (ps < 0.05). SIGNIFICANCE: Findings suggest that PWE are at risk for low health literacy, which may be partly attributable to disrupted brain-behavior relationships and contribute to poorer everyday functioning. Future studies are needed to identify effective methods to support and improve health literacy in PWE.

The role of lncRNAs related ceRNA regulatory network in multiple hippocampal pathological processes during the development of perioperative neurocognitive disorders.

Background: Perioperative neurocognitive disorders (PND) refer to neurocognitive abnormalities during perioperative period, which are a great challenge for elderly patients and associated with increased morbidity and mortality. Our studies showed that long non-coding RNAs (lncRNAs) regulate mitochondrial function and aging-related pathologies in the aged hippocampus after anesthesia, and lncRNAs are associated with multiple neurodegenerations. However, the regulatory role of lncRNAs in PND-related pathological processes remains unclear. Methods: A total of 18-month mice were assigned to control and surgery (PND) groups, mice in PND group received sevoflurane anesthesia and laparotomy. Cognitive function was assessed with fear conditioning test. Hippocampal RNAs were isolated for sequencing, lncRNA and microRNA libraries were constructed, mRNAs were identified, Gene Ontology (GO) analysis were performed, and lncRNA-microRNA-mRNA networks were established. qPCR was performed for gene expression verification. Results: A total of 312 differentially expressed (DE) lncRNAs, 340 DE-Transcripts of Uncertain Coding Potential (TUCPs), and 2,003 DEmRNAs were identified in the hippocampus between groups. The lncRNA-microRNA-mRNA competing endogenous RNA (ceRNA) network was constructed with 29 DElncRNAs, 90 microRNAs, 493 DEmRNAs, 148 lncRNA-microRNA interaction pairs, 794 microRNA-mRNA interaction pairs, and 110 lncRNA-mRNA co-expression pairs. 795 GO terms were obtained. Based on the frequencies of involved pathological processes, BP terms were divided into eight categories: neurological system alternation, neuronal development, metabolism alternation, immunity and neuroinflammation, apoptosis and autophagy, cellular communication, molecular modification, and behavior changes. LncRNA-microRNA-mRNA ceRNA networks in these pathological categories were constructed, and involved pathways and targeted genes were revealed. The top relevant lncRNAs in these ceRNA networks included RP23-65G6.4, RP24-396L14.1, RP23-251I16.2, XLOC_113622, RP24-496E14.1, etc., and the top relevant mRNAs in these ceRNA networks included Dlg4 (synaptic function), Avp (lipophagy), Islr2 (synaptic function), Hcrt (regulation of awake behavior), Tnc (neurotransmitter uptake). Conclusion: In summary, we have constructed the lncRNA-associated ceRNA network during PND development in mice, explored the role of lncRNAs in multiple pathological processes in the mouse hippocampus, and provided insights into the potential mechanisms and therapeutic gene targets for PND.

The role of anesthesia in peri­operative neurocognitive disorders: Molecular mechanisms and preventive strategies.

Peri-operative neurocognitive disorders (PNDs) include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Children and the elderly are the two populations most vulnerable to the development of POD and POCD, which results in both high morbidity and mortality. There are many factors, including neuroinflammation and oxidative stress, that are associated with POD and POCD. General anesthesia is a major risk factor of PNDs. However, the molecular mechanisms of PNDs are poorly understood. Dexmedetomidine (DEX) is a useful sedative agent with analgesic properties, which significantly improves POCD in elderly patients. In this review, the current understanding of anesthesia in PNDs and the protective effects of DEX are summarized, and the underlying mechanisms are further discussed.