HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

Crosstalk between gut microbiome and neuroinflammation in pathogenesis of HIV-associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) has become a chronic neurodegenerative disease affecting the quality of life in people living with HIV (PLWH). Despite an established association between HAND and neuroinflammation induced by HIV proteins (gp120, Tat, Rev., Nef, and Vpr), the pathogenesis of HAND remains to be fully elucidated. Accumulating evidence demonstrated that the gut microbiome is emerging as a critical regulator of various neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), suggesting that the crosstalk between the gut microbiome and neuroinflammation may contribute to the development of these diseases, for example, gut dysbiosis and microbiota-derived metabolites can trigger inflammation in the brain. However, the potential role of the gut microbiome in the pathogenesis of HAND remains largely unexplored. In this review, we aim to discuss and elucidate the HAND pathogenesis correlated with gut microbiome and neuroinflammation, and intend to explore the probable intervention strategies for HAND.

Systemic inflammation, neuroinflammation and perioperative neurocognitive disorders.

Perioperative neurocognitive disorder (PND) is a common disorder following anesthesia and surgery, especially in the elderly. The complex cellular and molecular processes are involved in PND, but the underlying pathogenesis of which remains inconclusive due to conflicting data. A growing body of evidence has been shown that perioperative systemic inflammation plays important roles in the development of PND. We reviewed the relevant literature retrieved by a search in the PubMed database (on July 20, 2023). The search terms used were "delirium", "post operative cognitive dysfunction", "perioperative neurocognitive disorder", "inflammation" and "systemic", alone and in combination. All articles identified were English-language, full-text papers. The ones cited in the review are those that make a substantial contribution to the knowledge about systemic inflammation and PNDs. The aim of this review is to bring together the latest evidence for the understanding of how perioperative systemic inflammation mediates neuroinflammation and brain injury, how the inflammation is regulated and how we can translate these findings into prevention and/or treatment for PND.

Reversible large-scale network disruption correlates with neurocognitive improvement in HIV-associated minor neurocognitive disorder with combined anti-retroviral therapy intensification: a prospective longitudinal resting-state functional magnetic resonance imaging study.

OBJECTIVE: HIV-associated neurocognitive disorder (HAND) affects multiple cognitive domains and currently, the neuropsychological testing is the gold standard to identify these deficits. The aim of this longitudinal 12-month pilot study is to determine the effect of intensified combination antiretroviral therapy (cART) on rs-fMRI in virally suppressed (both in CSF and blood) patients with active HAND (those who have progressive neurocognitive impairment) and correlated with neurocognitive function tests. METHODS: In this pilot study, we have evaluated sixteen patients with active HAND with viral suppression in both blood and CSF to study the effect of cART on functional connectivity. Participants underwent rs-fMRI at the baseline (time point-1 (TP-1) and 12-month visits (time point-2 (TP-2)). Connectivity in the five major networks was measured at TP-1 and TP-2 using the seed-based approach. All the participants underwent a five-domain neuropsychological battery at TP-1 and TP-2. Neurocognitive scores (NC) as well as blood and CSF markers were correlated with functional connectivity (FC). RESULTS: There was a significant increase in the FC between the two time points within the executive, salience, default mode, dorsal attention, and visual networks at voxel level threshold of p < 0.001 and cluster level threshold of p < 0.05 and corrected for false detection rate (FDR). The neurocognitive scores were positively correlated with all the networks at similar cluster and voxel level thresholds. CONCLUSIONS: These results indicate that rs-fMRI can be potentially used as one of the biomarkers for treatment efficacy in HAND.

Diversity in verbal fluency performance and its associations with MRI-informed brain age matrices in normal ageing and neurocognitive disorders.

INTRODUCTION: Category verbal fluency test (CVFT) has been widely used to assess and monitor the cognitive capacities in epidemiological studies and clinical trials. Pronounced discrepancy in CVFT performance has been found in individuals with different cognitive statuses. This study aimed to combine the psychometric and morphometric approaches to decode the complex verbal fluency performance in senior adults with normal ageing and neurocognitive disorders. METHODS: This study adopted a two-stage cross-sectional design involving quantitative analyses of neuropsychological and neuroimaging data. In study I, capacity- and speed-based measures of CVFT were developed to evaluate the verbal fluency performance in normal ageing seniors (n = 261), those with mild cognitive impairment (n = 204), and those with dementia (n = 23) whose age range is from 65 to 85 years. In study II, structural magnetic resonance imaging-informed gray matter volume (GMV) and brain age matrices were calculated in a subsample (n = 52) from Study I through surface-based morphometry analysis. With age and gender as covariates, Pearson's correlation analysis was used to examine the associations of CVFT measures, GMV, and brain age matrices. RESULTS: Speed-based measures showed extensive and stronger associations with other cognitive functions than capacity-based measures. The component-specific CVFT measures showed shared and unique neural underpinnings with lateralized morphometric features. Moreover, the increased CVFT capacity was significantly correlated with younger brain age in mild neurocognitive disorder (NCD) patients. CONCLUSION: We found that the diversity of verbal fluency performance in normal ageing and NCD patients could be explained by a combination of memory, language, and executive abilities. The component-specific measures and related lateralized morphometric correlates also highlight the underlying theoretical meaning of verbal fluency performance and its clinical utility in detecting and tracing the cognitive trajectory in individuals with accelerated ageing.

Differential expression of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Alzheimer's disease and HIV-1 associated neurocognitive disorders.

The United Nations projects that one in every six people will be over the age of 65 by the year 2050. With a rapidly aging population, the risk of Alzheimer's disease (AD) becomes a major concern. AD is a multifactorial disease that involves neurodegeneration in the brain with mild dementia and deficits in memory and other cognitive domains. Additionally, it has been established that individuals with Human Immunodeficiency Virus-1 (HIV-1) experience a 5 to 10-year accelerated aging and an increased risk of developing HIV-associated neurocognitive disorders (HAND). Despite a significant amount of clinical evidence pointing towards a potential overlap between neuropathogenic processes in HAND and AD, the underlying epigenetic link between these two diseases is mostly unknown. This study is focused on identifying differentially expressed genes observed in both AD and HAND using linear regression models and a more robust significance analysis of microarray. The results established that the dysregulated type 1 and 2 interferon pathways observed in both AD and HAND contribute to the similar pathologies of these diseases within the brain. The current study identifies the important roles of interferon pathways in AD and HAND, a relationship that may be useful for earlier detection in the future.

Elevation of brain ADC (apparent diffusion coefficient) in HIV-associated neurocognitive disorders and evolution after treatment: A pilot study.

BACKGROUND: Thirty to 50% of HIV-infected patients develop HIV-Associated Neurocognitive Disorders (HAND) despite virological control. The previously published Neuro+3 study showed their neurocognitive status can be improved by intensifying antiviral therapy. Our study is a part of the Neuro3+ study and aims to study apparent diffusion coefficient (ADC) as a biomarker for neurological improvement. PATIENTS AND METHODS: We prospectively included 31 patients with HAND. They received therapy with better CNS Penetration Effectiveness (CPE) score with two-year follow-up. Cognitive status was assessed at day 0 (D0) and week 96 (W96) using Frascati 3-stage classification and Global Deficit Score (GDS). Brain MRI at D0 and W96 assessed morphological data (white matter hyperintensities, opportunistic infections, ischemic lesions, atrophy) and measured whole brain apparent diffusion coefficient (ADC). We compared their data with a control group of 20 healthy patients with similar ages and sex ratio. RESULTS: After ARV intensification, cognitive status was significantly improved: GDS (n = 1,4 vs 1,0 p = 0.01) and Frascati scale (2HAD/22MND/7ANI vs 1HAD/8MND/17ANI p = 0.001). Mean ADC was significantly higher in patients at inclusion than in controls (0.88 × 10-3 mm2/s ± 0.06 vs 0.81 × 10-3 mm2/s ± 0.04, p = 0.0001). ADC decreased after treatment (0.88 × 10-3 mm2/s ± 0.06 vs 0.85 × 10-3 mm2/s ± 0.06 (p = 0,04). In subgroup analysis, ADC significantly decreased in clinically improved patients (0.89 × 10-3 mm2/s ± 0.07 vs 0.85 × 10-3 mm2/s ± 0.07 (p = 0,03)) and did not significantly change in non-clinically improved patients (0.86 × 10-3 mm2/s ± 0.07 vs 0.84 × 10-3 mm2/s ± 0.07 (p = 0,31)). After treatment, there was no significant difference between patients and controls (0.85 × 10-3 mm2/s ± 0.06 vs 0.81 × 10-3 mm2/s ± 0.04, p = 0.17). CONCLUSION: Whole-brain ADC is a good biomarker of HIV-associated neurocognitive disorders. It is significantly increased in patients with HAND compared with controls and significantly decreases after treatment. It is all the more important to have a quantitative biomarker as conventional imaging does not contribute to the diagnosis.

Transcranial Photobiomodulation Therapy Ameliorates Perioperative Neurocognitive Disorder Through Modulation of Mitochondrial Function in Aged Mice.

Perioperative neurocognitive disorder (PND) is a serious nervous system complication characterized by progressive cognitive impairment, especially in geriatric population. However, the neuropathogenesis of PND is complex, and there are no approved disease-modifying therapeutic options. Mitochondrial dysfunction has been demonstrated to contribute to the occurrence and development of PND. Transcranial near-infrared (tNIR) light treatment helps to improve mitochondrial dysfunction and enhance cognition, but its effect on PND remains unclear. Here, we evaluated the effect of tNIR light treatment on PND caused by anesthesia and surgery in aged mice. We built the PND models with 18-month C57BL/6 male mice by exploratory laparotomy under isoflurane inhalation anesthesia, and treated by tNIR light with wavelength 810 nm for 2 weeks. The short-term and long-term changes in cognitive function were analyzed by behavioral tests. We further explored the effects of tNIR light on mitochondria, synapses, neurons, and signaling pathways through different experimental methods. The results demonstrated that the cognitive impairment and mitochondrial dysfunction in PND mice were ameliorated after tNIR light treatment. Further experiments demonstrated that photobiomodulation therapy (PBMT) increased synapse-related protein expression, neuronal survival, and protected synapse from depletion. Moreover, downregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) were increased after tNIR light treatment. Our results suggested that tNIR light was an effective treatment of PND through PBMT effect, accompanied by synaptic and neuronal improvement. The improvement of mitochondrial dysfunction mediated by SIRT1/PGC-1α signaling pathway might participate in this process. Those findings might provide a novel and noninvasive therapeutic target for PND.

Effect of changes in cerebral oximeter values during cardiac surgery on the incidence of postoperative neurocognitive deficits (POND): A retrospective study based on propensity score-matched analysis.

OBJECTIVES: The occurrence of postoperative neurocognitive deficits(POND)after major cardiac surgery is associated with an increase in perioperative mortality and morbidity. Oxidative stress caused by oxygen can affect neuronal damage, which can lead to POND. Whether the intraoperative rSO2 value reflects oxidative stress and the associated incidence of POND is unknown. METHODS: Among 3482 patients undergoing cardiac surgery, 976 patients were allocated for this retrospective study. Of these, 230 patients (32.5%) were observed to have postoperative neurologic symptoms. After propensity score 1:2 ratio matching, a total of 690 patients were included in the analysis. Recorded data on the occurrence of POND from the postoperative period to predischarge were collected from the electronic records. RESULTS: The mean baseline rSO2 value was higher in the POND (-) group than in the POND (+) group. The mean overall minimum rSO2 value was lower in the POND (+) group (52.2 ± 8.3 vs 48.3 ± 10.5, P < 0.001). The mean overall maximum rSO2 values were not significantly different between the two groups (72.7 ± 8.3 vs 73.2 ± 9.2, P = 0.526). However, there was a greater increase in the overall maximum rSO2 values as compared with baseline in the POND (+) group (10.9 ± 8.2 vs 17.9 ± 10.2, P < 0.001). The degree of increase in the maximum rSO2 value was a risk factor affecting the occurrence of POND (adjusted odds ratio, 1.08; 95% confidence interval [CI], 1.04-1.11; P < 0.001). The areas under the receiver-operating characteristic curve for delta values of minimal and maximal compared with baseline values were 0.60 and 0.71, respectively. CONCLUSIONS: Increased cerebral oximeter levels during cardiac surgery may also be a risk factor for POND. This is considered to reflect the possibility of oxidative neuronal damage, and further studies are needed in the future.

High-Mobility Group Box-1 and Its Potential Role in Perioperative Neurocognitive Disorders.

Aseptic surgical trauma provokes the release of HMGB1, which engages the innate immune response after binding to pattern-recognition receptors on circulating bone marrow-derived monocytes (BM-DM). The initial systemic inflammation, together with HMGB1, disrupts the blood-brain barrier allowing penetration of CCR2-expressing BM-DMs into the hippocampus, attracted by the chemokine MCP-1 that is upregulated by HMGB1. Within the brain parenchyma quiescent microglia are activated and, together with the translocated BM-DMs, release proinflammatory cytokines that disrupt synaptic plasticity and hence memory formation and retention, resulting in postoperative cognitive decline (PCD). Neutralizing antibodies to HMGB1 prevents the inflammatory response to trauma and PCD.

Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

Activation of CD200-CD200R1 Axis Attenuates Perioperative Neurocognitive Disorder Through Inhibition of Neuroinflammation in Mice.

Perioperative neurocognitive disorder (PND) is the mild cognitive impairment associated with surgery and anesthesia. It is a common surgical complication in the elderly. An important mechanism of PND is the surgically induced neuroinflammation. The interaction between the neuronal surface protein CD200 and its receptor in microglia, CD200R1, is an important regulatory pathway to control neuroinflammation. However, the potential role of the CD200-CD200R1 pathway in the acute period of PND has not been fully investigated. In this study, in a PND mouse model, we first measured the protein expression level of CD200, CD200R1, and the related pro- and anti-inflammatory cytokines in the hippocampus. Then, we investigated cognitive function, neuroinflammation and postsynaptic density protein 95 (PSD-95) expression after the injection of CD200-Fc (agonist), CD200R1-Fc (antagonist) or IgG1-Fc (vehicle) into lateral ventricle in PND models. Compared with the control group, the expression of CD200 was up-regulated at day 1 after surgery in PND models. The injection of the CD200-Fc into the lateral ventricle could mitigate primed neuroinflammation and cognitive decline, increase the expression of PSD-95 at day 1 after surgery in PND models. In conclusion, we have demonstrated that CD200-CD200R1 signaling was involved in the acute inflammatory process of PND, and activating CD200R1 can inhibit neuroinflammation and attenuate PND. Thus, the CD200-CD200R1 axis is a potential novel target for PND prevention and treatment.

The Effect of Hippocampal Avoidance Whole Brain Radiotherapy on the Preservation of Long-Term Neurocognitive Function in Non-Small Cell Lung Cancer Patients With Brain Metastasis.

Whole-brain radiotherapy (WBRT) is the mainstay of therapy in treating cancer patients with brain metastases, but unfortunately, it might also lead to decline in neurocognitive function. This study aims to investigate the preservation of long-term neurocognitive function in patients after hippocampal avoidance whole-brain radiotherapy (HA-WBRT). Retrospectively, 47 patients diagnosed with brain metastases of non-small cell lung cancer (NSCLC) between 2015-01-01 and 2017-12-31 at the Department of Oncology, XXX Hospital were selected and divided into 2 groups. Group A (n = 27) received HA-WBRT, whereas group B (n = 20) received WBRT. Neurocognitive function was analyzed at baseline and at 3, 6, 9, 12 and 24 months after radiotherapy, using Mine-Mental State Examination (MMSE) scales and Montreal Cognitive Assessment (MoCA) scales. The OS, PFS and tumor recurrence sites were also analyzed. When evaluated at 12 and 24 months after radiotherapy, the cognitive function scores of the hippocampal avoidance group were significantly higher than those of the non-hippocampal avoidance group (P < 0.001). In terms of patient survival, there was no significant difference in OS (P = 0.2) and PFS (P = 0.18) between these 2 groups. Fourteen patients in group A and 12 patients in group B had brain tumor recurrence after radiation, only one patient in group A occurred within 5 mm from the edge of the hippocampus (P > 0.05). In conclusion, HA-WBRT might have a protective effect on long-term neurocognitive function and did not affect patient survival.

Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort.

PURPOSE: Eight percent of young-adult childhood cancer survivors meet criteria for frailty, an aging phenotype associated with poor health. In the elderly general population, frailty is associated with neurocognitive decline; this association has not been examined in adult survivors of childhood cancer. METHODS: Childhood cancer survivors 18-45 years old (≥ 10 years from diagnosis) were clinically evaluated for prefrailty or frailty (respectively defined as ≥ 2 or ≥ 3 of: muscle wasting, muscle weakness, low energy expenditure, slow walking speed, and exhaustion [Fried criteria]) and completed neuropsychologic assessments at enrollment (January 2008-June 2013) and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS-directed therapy (cranial radiation, intrathecal chemotherapy, and neurosurgery), and baseline neurocognitive performance. RESULTS: Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrollment. Frail survivors declined an average of 0.54 standard deviation (95% CI, -0.93 to -0.15) in short-term verbal recall, whereas nonfrail survivors did not decline (ß = .22; difference of ßs = -.76; 95% CI, -1.19 to -0.33). Frail survivors declined more than nonfrail survivors on visual-motor processing speed (ß = -.40; 95% CI, -0.67 to -0.12), cognitive flexibility (ß = -.62; 95% CI, -1.02 to -0.22), and verbal fluency (ß = -.23; 95% CI, -0.41 to -0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail ß = -.35; 95% CI, -0.53 to -0.17; frail ß = -.48; 95% CI, -0.83 to -0.12) compared with nonfrail survivors. CONCLUSION: Over approximately 5 years, prefrail and frail young-adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Interventions that have global impact, designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.

Ginkgolide B­mediated therapeutic effects on perioperative neurocognitive dysfunction are associated with the inhibition of iNOS­mediated production of NO.

Perioperative neurocognitive dysfunction (PND) is a prevalent neurological complication after anesthesia and surgery. Ginkgolide B (GB) has been suggested to improve lipopolysaccharide­induced learning and memory impairment. The present study aimed to investigate whether GB serves a protective role against PND by inhibiting inducible nitric oxide synthase (iNOS) and nitric oxide (NO). Abdominal surgery was performed on 10­ to 12­week­old male C57BL/6 mice under isoflurane anesthesia. Prior to surgery, 1400W (a specific iNOS inhibitor) and GB were administered via intraperitoneal injection. Open field and fear conditioning tests were conducted to assess cognitive function on postoperative days 1 and 3. Biochemical assays were performed to evaluate alterations in NO, malondialdehyde (MDA) and superoxide dismutase (SOD) levels. Western blotting was performed to measure iNOS expression in the hippocampus on postoperative day 1. In addition, hematoxylin and eosin staining was performed to detect the neuronal morphology in the hippocampus. Following treatment with 1400W or GB, surgery­induced cognitive dysfunction was improved. Compared with the control group, the surgery group exhibited significant overproduction of iNOS and MDA in the hippocampus on postoperative day 1. Higher levels of NO were also detected in the hippocampus and prefrontal cortex of the surgery group on postoperative day 1. Furthermore, pretreatment with 1400W or GB significantly inhibited the surgery­induced elevation of NO and MDA in brain tissues. Moreover, GB pretreatment significantly inhibited surgery­induced downregulation of SOD and upregulation of iNOS. Surgery­induced increases in neuronal loss and the Bax/Bcl­2 ratio in the hippocampus were significantly inhibited by pretreatment with GB. Collectively, the results of the present study demonstrated that the therapeutic effects of GB on PND were associated with inhibition of iNOS­induced NO production, increased SOD, and the alleviation of neuronal loss and apoptosis.

Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice.

INTRODUCTION: The incidence of perioperative neurocognitive disorders (PND) is higher in the elderly patients undergoing surgery. Microglia activation-mediated neuroinflammation is one of the hallmarks of PND. Galectin-1 has been identified as a pivotal modulator in the central nervous system (CNS), while the role of galectin-1 in PND induced by microglia-mediated neuroinflammation is still undetermined. METHODS: An exploratory laparotomy model anesthetized with isoflurane was employed to investigate the role of galectin-1 on PND in aged mice. Open field test and Morris water maze were used to test the cognitive function 3- or 7-days post-surgery. The activation of microglia in the hippocampus of aged mice was tested by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the underlying mechanisms. RESULTS: Galectin-1 attenuated the cognitive dysfunction induced by surgery in aged mice and inhibited microglial activity. Moreover, galectin-1 decreased the expression level of inflammatory proteins (interleukin-1ß, interleukin-6, and tumor necrosis factor-α), and prevented neuronal loss in the hippocampus. Galectin-1 inhibited the inflammation of BV2 microglial cells induced by lipopolysaccharide via decreasing the translocation of NF-κB p65 and c-Jun, while this kind of inhibition was rescued when overexpressing IRAK1. CONCLUSION: Our findings provide evidence that galectin-1 may inhibit IRAK1 expression, thus suppressing inflammatory response, inhibiting neuroinflammation, and improving ensuing cognitive dysfunction. Collectively, these findings unveil that galectin-1 may elicit protective effects on surgery-induced neuroinflammation and neurocognitive disorders.

Natural Bioactives as Potential Therapeutic Modalities Against NeuroAIDS.

With the introduction of antiretroviral therapy, the worldwide AIDS-related deaths have decreased, and life expectancy has increased, including the prevalence of AIDS-related neurological disorders or neuroAIDS. HIV-associated neurocognitive disorders such as mild neurocognitive disorder and asymptomatic neurocognitive impairment have largely remained stable or increased among the HIV-infected individuals in the combination antiretroviral therapy era. The emerging evidence that antiretrovirals with high CNS penetration effectiveness score contribute to the neurotoxicity and HIV-associated neurocognitive disorders has ushered the search for natural, nontoxic bioactive constituents having pre-established neuroprotective, anti-inflammatory, and restorative neurocognitive activity. In this review, we have highlighted the probable mechanism of neuroAIDS infection, the problem with the existing antiretroviral therapy, along with various bioactive constituents with in vivo, in vitro, or ex vivo evidence of their neuroprotective activity that can be used as an adjuvant with the current combination antiretroviral therapy regimen or can even serve as an alternate to the antiretrovirals for treatment of HIV associated neurocognitive disorder.

Neurocognitive impairment and health-related quality of life among people living with Human Immunodeficiency Virus (HIV).

The association between HIV-associated neurocognitive impairment (NCI) and health-related quality of life (HRQoL) is not well known. We investigated this association among the CNS (Central Nervous System) HIV Antiretroviral Therapy Effects Research (CHARTER) study participants. We performed factor analysis to distinguish physical and mental HRQoL, followed by general linear models. We analyzed 1,340 HIV participants, including 35.6% with NCI, 77.2% males, 70.5% unemployed, and 42.2% with depression. Impaired participants had lower (worse) mental and physical HRQoL mean scores compared to unimpaired participants. NCI was negatively associated with mental HRQoL in crude (mean difference: -4.38; 95% CI: -6.70 to -2.06) and adjusted analysis (-2.56, -4.83 to -0.30). NCI was also negatively associated with physical HRQoL in unadjusted analysis (-4.62, -7.45 to -1.78), though the association weakened in the adjusted analysis (-2.20, -4.81 to 0.40). The association between NCI and HRQoL was confounded mainly by employment and was partially mediated by depression. These findings suggest that future strategies aimed at improving HRQoL among HIV-infected patients with NCI might benefit from concurrent management of depression.

Neurocognitive Effects of Chemotherapy for Colorectal Cancer: A Systematic Review and a Meta-Analysis of 11 Studies.

PURPOSE: Chemotherapy-related cognitive impairment (CRCI) is a controversial concept not much explored on colorectal cancer patients. MATERIALS AND METHODS: We identified 11 prospective studies: eight studies on 696 colorectal cancer patients who received chemotherapy and three studies on 346 rectal cancer patients who received neoadjuvant chemoradiotherapy. Standardized mean differences (SMDs) of neuropsychological test results and the cognitive quality-of-life scale were calculated using random effect models. A meta-regression was conducted to investigate the association between mean study population age and effect sizes. RESULTS: The association between chemotherapy and cognitive impairment was not clear in colorectal cancer patients (SMD, 0.003; 95% confidence interval, ‒0.080 to 0.086). However, a meta-regression showed that older patients are more vulnerable to CRCI than younger patients (ß=‒0.016, p < 0.001). CONCLUSION: Chemotherapy has an overall positive negligible effect size on the cognitive function of colorectal patients. Age is a significant moderator of CRCI.