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Background Neurocognitive disorders are prevalent among older surgical patients, yet their underlying mechanisms and effective interventions remain largely unknown. Studies in rodents and patients suggest a connection between olfactory impairment and perioperative neurocognitive disorder (PND). Previous work in mice demonstrates that anesthesia and surgery can lead to both olfactory impairment and cognitive deficits. Olfactory enrichment, which is also referred to as olfactory training (i.e., daily exposure to multiple odorants), may prove helpful. For example, olfactory enrichment appears to reduce PND-like behaviors in mice, possibly by mitigating anesthesia- and surgery-induced reductions in olfactory receptor neurons. Additionally, olfactory enrichment increases the volume and size of olfactory-related brain regions, such as the olfactory bulb and hippocampus, as well as changes in functional connectivity in non-surgical adults. Despite promising findings in mice, it remains unknown whether olfactory training reduces PND in surgical patients. We therefore propose a randomized clinical trial. Methods and analysis This sham-controlled assessor-blind randomized controlled trial will enroll 686 patients aged 65 and older who are scheduled for orthopedic Surgery expected to last at least 2h under general anesthesia. Participants will be randomized 1:1 to olfactory enrichment or sham treatment. Those assigned to the olfactory enrichment group will receive twice-daily 30-min sessions involving four distinct odors, beginning on 1 day before surgery and continuing for three postoperative days during hospitalization. Patients assigned to sham treatment will follow the same schedule, but with odorless substances in the scent dispenser. The primary outcome is the incidence of postoperative delirium, assessed using the 3-min diagnostic interview for CAM-defined delirium (3D-CAM) on postoperative days 1, 2, and 3. Secondary outcomes include the incidence of delayed neurocognitive recovery and postoperative neurocognitive disorder, evaluated through cognitive function assessments using neuropsychological tests at baseline, 21 days, and 6 months after the anesthesia/surgery. Exploratory outcomes include the severity of delirium measured by the CAM-severity (CAM-S) tools, the severity of delayed neurocognitive recovery and postoperative neurocognitive disorder assessed through neuropsychological tests, evaluations of activities of daily living, plasma Tau-PT217 levels, and olfactory function. Discussion This is the first clinical trial to evaluate the efficacy of olfactory enrichment in geriatric patients undergoing orthopedic surgery, filling an important gap in the treatment evidence for PND. Trial registration The trail has been registered in ClinicalTrial.gov with the Trial Registration Number of NCT06488807. Date of registration in the primary registry: June 15, 2024. The study is anticipated to start in March 2025. The anticipated primary completion date is December 31, 2027. 

Abstract Background Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment. Methods The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations. Results Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168. Conclusions Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments. Clinical Trials Registration NCT00096824. AIDS Clinical Trials Group A5199 compared the neurological and neuropsychological results in 860 human immunodeficiency virus-positive participants from seven resource limited countries randomized on 3 antiretroviral regimens. Participants showed improved neurocognitive function following antiretroviral therapy initiation compared to normative data.

Background Perioperative neurocognitive dysfunction (PND), a prevalent complication affecting elderly surgical patients, poses substantial challenges to postoperative rehabilitation and long-term functional independence. Despite growing awareness of its clinical significance, current evidence regarding effective neuroprotective anesthetic strategies remains inconclusive. Where emerging evidence suggests opioid-free anesthesia (OFA) strategies could maintain analgesic efficacy while potentially attenuating opioid-associated neuroinflammatory mechanisms implicated in PND pathogenesis. This multicenter trial investigates the efficacy of OFA combined with ultrasound-guided iliofascial nerve block in mitigating PND among geriatric patients undergoing hip fracture surgery. Methods This multicenter, randomized controlled trial will enroll 348 patients, who will be randomly assigned to receive either OFA combined with iliofascial nerve block or opioid-based anesthesia (OBA) combined with iliofascial nerve block. All patients will undergo hip fracture surgery under general anesthesia with tracheal intubation. The primary outcome will be the change in composite neurocognitive scores, assessed through a battery of neuropsychological tests from baseline to 3 months postoperatively. Secondary outcomes include alterations in serum protein and inflammatory markers, extubation time, postoperative pain incidence, intraoperative hemodynamic stability, and postoperative recovery parameters. The safety profile of OFA in hip surgery will also be assessed. Discussion Effective prevention of PND is crucial for optimizing postoperative recovery and long-term functional outcomes in elderly patients. This trial aims to refine and optimize anesthesia management strategies to reduce the incidence of PND, improve postoperative quality of life, and ultimately enhance perioperative neurocognitive outcomes. Trial registration This trial protocol was registered with the China Clinical Trial Registry on December 14, 2023, under the registration number: ChiCTR2300078647.

Key Points Social cognitive deficits are prominent in many conditions and are critical predictors of functional outcomes because they affect the ability to form and sustain interpersonal relationships Assessments of social cognitive impairments typically focus on theory of mind, affective empathy, social perception and social behaviour, four domains that all influence the management of a patient Many social cognitive assessment measures that are appropriate for clinical use are now available and should form part of a broader neurocognitive battery Common disorders that manifest with prominent social cognitive deficits include schizophrenia, autism spectrum disorders, Alzheimer disease, and behavioural-variant frontotemporal dementia A range of effective treatment strategies are currently available, so the nature, magnitude and specificity of social cognitive impairments each have important implications for therapeutic decision-making Many neurological disorders, from traumatic brain injury to Alzheimer disease, affect social cognition, yet deficits in social cognition can be difficult to detect and diagnose effectively. In this Review, Henry and colleagues provide an overview of the clinical contexts in which social cognitive dysfunction arises and consider how tests can be used to detect it. Through examples of four conditions in which social cognitive dysfunction arises, they demonstrate the appropriate tests to use, and consider their clinical application beyond these disorders. Social cognition broadly refers to the processing of social information in the brain that underlies abilities such as the detection of others' emotions and responding appropriately to these emotions. Social cognitive skills are critical for successful communication and, consequently, mental health and wellbeing. Disturbances of social cognition are early and salient features of many neuropsychiatric, neurodevelopmental and neurodegenerative disorders, and often occur after acute brain injury. Its assessment in the clinic is, therefore, of paramount importance. Indeed, the most recent edition of the American Psychiatric Association's Diagnostic and Statistical Manual for Mental Disorders (DSM-5) introduced social cognition as one of six core components of neurocognitive function, alongside memory and executive control. Failures of social cognition most often present as poor theory of mind, reduced affective empathy, impaired social perception or abnormal social behaviour. Standard neuropsychological assessments lack the precision and sensitivity needed to adequately inform treatment of these failures. In this Review, we present appropriate methods of assessment for each of the four domains, using an example disorder to illustrate the value of these approaches. We discuss the clinical applications of testing for social cognitive function, and finally suggest a five-step algorithm for the evaluation and treatment of impairments, providing quantitative evidence to guide the selection of social cognitive measures in clinical practice.

The prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, IMT and Fibroscan measurements were performed. After 1:1 randomization to a less neurotoxic regimen consisting of darunavir/cobicistat plus emtricitabine plus maraviroc, or mantaining actual care, tests were repeated after 24 weeks: CSF biomarkes (HIV RNA, tau, p-tau, Beta-amyloid 1-42 , S100Beta and neopterin) were included. Non-parametric tests (Mann–Whitney and Wilcoxon’s) were used. 28 participants completed the study. Male and European ancestry were prevalent; median age was 55 years (51–60). All patients were virally suppressed; median CD4 + count was 626 cell/uL (469–772). Baseline characteristics were similar between the study arms. A significant decrease in CSF p-tau and an increase in CSF neopterin and NFL were observed. We observed a significant reduction in liver stiffness at W24. Despite a small sample size we observed changes in neuromarkers and in hepatic stiffness in patients randomized to the experimental arm. We observed changes in CSF biomarkers (lower phosphorylated-tau and higher neopterin and NFL) that need to be replicated in large cohorts. Subclinical neurotoxicity may be observed in patients with HAND and warrants prospective studies. Graphical Abstract

Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.

Perioperative neurocognitive disorders (NCDs) refer to neurocognitive abnormalities detected during the perioperative periods, including preexisting cognitive impairment, preoperative delirium, delirium occurring up to 7 days after surgery, delayed neurocognitive recovery, and postoperative NCD. The Diagnostic and Statistical Manual of Mental Disorders‐5th edition (DSM‐5) is the golden standard for diagnosing perioperative NCDs. Given the impracticality of using the DSM‐5 by non‐psychiatric practitioners, many diagnostic tools have been developed and validated for different clinical scenarios. The etiology of perioperative NCDs is multifactorial and includes predisposing and precipitating factors. Identifying these risk factors is conducive to preoperative risk stratification and perioperative risk reduction. Prevention for perioperative NCDs should include avoiding possible contributors and implementing nonpharmacologic and pharmacological interventions. The former generally includes avoiding benzodiazepines, anticholinergics, prolonged liquid fasting, deep anesthesia, cerebral oxygen desaturation, and intraoperative hypothermia. Nonpharmacologic measures include preoperative cognitive prehabilitation, comprehensive geriatric assessment, implementing fast‐track surgery, combined use of regional block, and sleep promotion. Pharmacological measures including dexmedetomidine, nonsteroidal anti‐inflammatory drugs, and acetaminophen are found to have beneficial effects. Nonpharmacological treatments are the first‐line measures for established perioperative NCDs. Pharmacological treatments are still limited to severely agitated or distressed patients. Perioperative neurocognitive disorders constitute a great challenge for older patients scheduled for surgery because their occurrence is associated with increased morbidity and mortality as well as enormous medical costs. Preoperative risk stratification and perioperative risk reduction should be adopted for perioperative NCDs prevention and treatment.

Background The complement system plays an important role in many neurological disorders. Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND. Methods A stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker. Results C3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function. Conclusions Orthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.

Background: The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite antiretroviral treatment (ART). Changes in gut microbiota and persistent immune activation have been suggested as possible causes, while the role of probiotic supplementation remains controversial. Methods: We included subjects with mild HAND and successful ART. They were randomized to receive either 6 months of high-dose probiotic supplementation or to continue with only ART. Immune activation markers and neuropsychological testing were performed at baseline and the end of follow-up. Neuropsychological testing assessed learning, episodic memory, attention/concentration, executive functions, language, information processing speed, and motor skills. Z- and T-scores were calculated for all domains but motor skills, allowing the measurement of the global deficit score (GDS). The trajectories of neuropsychological performances and immune activation markers were compared between groups. Results: From September 2020 to July 2021, 31 PWHs were included (median age 62, 73% men, CD4 744 cc/mm3), and 28 completed the 6-month follow-up. The characteristics of the subjects and their neuropsychological performance at baseline in the two groups were similar. At the end of follow-up, probiotics did not have any impact on immune activation markers, while they were associated with better improvement in GDS (T-score 0.0 in controls vs. −0.3 in probiotics, p = 0.048) and the attention/concentration test (Z-score 0.4 in controls vs. 1.2 in probiotics, p = 0.035). Conclusions: Oral supplementation with high-dose probiotics for 6 months did not affect systemic immune activation but was associated with improved neurocognitive performance, suggesting benefits from probiotic supplementation for mild HAND.