Improvement Of Cognitive Dysfunction Research Articles

Milk Fat Globule-EGF Factor 8 (MFGE8) Mitigates Cognitive Impairment in Rats with Sepsis-Associated Encephalopathy: An fMRI Study.

Sepsis-associated encephalopathy (SAE) impairs hippocampal microglial efferocytosis, causing cognitive deficits. Previous research found that milk fat globule epidermal growth factor 8 protein (MFGE8) stimulates efferocytosis, reducing hippocampal inflammation in SAE rats. In this study, we explore MFGE8's role in alleviating cognitive impairment and its impact on neural activity using functional magnetic resonance imaging (fMRI). Sixty male Sprague Dawley rats were divided into four groups: Sham, cecal ligation and puncture (CLP), CLP+MFGE8, and CLP+MFGE8+CGT (Cilengitide). After CLP, CLP+MFGE8 rats received intracerebroventricular MFGE8 (3.3 µg), while CLP+MFGE8+CGT rats received intraperitoneal Cilengitide (10 mg/kg). We assessed cognitive function with the Morris water maze and open field test over five days. Eight days post-surgery, rats underwent T2-weighted magnetic resonance imaging (MRI) and resting state (rs)-fMRI scans. Brain tissues were collected for western blot, hematoxylin-eosin (HE) staining, and immunofluorescence. Statistical analysis employed one-way analysis of variance (ANOVA) followed by Tukey's post-test for multiple comparisons. MFGE8 improved neurobehavioral performance in open field task (OFT) and morris water maze (MWM) tests. fMRI indicated a significant reduction in abnormal neural activity in the right hippocampal CA1, CA3, and dentate gyrus of SAE rats following MFGE8 treatment. Voxel-based morphometry (VBM) analysis revealed decreased high-signal areas in the hippocampus, along with reduced hippocampal volume due to alleviated neural edema. Western blot analysis demonstrated that MFGE8 enhanced ras-related C3 botulinum toxin substrate 1 (Rac1) and microtubule-associated protein 1A/1B-light chain 3 (LC3) expression in the rat hippocampus, while CGT reduced these protein levels. Behavioral experiments and fMRI results confirmed that CGT reversed the cognitive effects of MFGE8 by inhibiting microglial αVβ3/αVβ5 integrin receptors. Our findings show that MFGE8 reduced amplitude of low-frequency fluctuations (ALFF) values in the right hippocampal CA1, CA3, and the dentate gyrus, mitigating abnormal neural activity and decreasing hippocampal volume. This led to an improvement in cognitive dysfunction in SAE rats. These results suggest that MFGE8 enhances microglial efferocytosis by activating αVβ3 and αVβ5 integrin receptors on microglial surfaces, ultimately improving cognitive function in SAE rats.

Iodine-123-Iomazenil Single-Photon Emission Computed Tomography Revealed Recovery of Neuronal Viability in Association With Improvement of Cognitive Dysfunction After Revascularization in Moyamoya Disease.

Recent studies indicate that 123I-iomazenil (123I-IMZ) single-photon emission computed tomography (SPECT) can demonstrate neuronal viability. Although cognitive dysfunction has been recognized as an important issue in adult patients with moyamoya disease (MMD), no standard neuroradiological methods to define such conditions have been established. We examined the relationship between cognitive function and 123I-IMZ SPECT before and after revascularization in patients with MMD. The study participants were 16 adult patients with MMD whose cerebrovascular reactivities were decreased only on the surgical sides of combined revascularization. Cognitive function was examined using the Mini-Mental State Examination (MMSE; cutoff: 27) and the Frontal Assessment Battery (FAB; cutoff: 16) before and at 3 to 6 months after surgery. 123I-iodoamphetamine (123I-IMP) SPECT with acetazolamide challenge and 123I-IMZ SPECT were performed concurrently while evaluating cognitive function. The radioreactivities of 123I-IMZ SPECT in regions with decreased cerebrovascular reactivities on 123I-IMP SPECT were investigated using affected-to-contralateral side asymmetry ratio (IMZ-ACR). Twelve patients showed normal cognitive function (MMSE: 29.8 ± 0.4, FAB: 18 ± 0) before surgery. No evident laterality of 123I-IMZ uptake was seen (IMZ-ACR: 0.98 ± 0.04). Neither cognitive function nor 123I-IMZ SPECT worsened after surgery (MMSE: 29.8 ± 0.3, FAB: 18 ± 0, IMZ-ACR: 1.00 ± 0.04). By contrast, 4 patients presented cognitive dysfunction (MMSE: 24.3 ± 3.9, FAB: 14.8 ± 2.7) before revascularization. Preoperative imaging of these patients showed decreased 123I-IMZ uptake, and their IMZ-ACRs (0.83 ± 0.08) were significantly lower than those of the normal group. After revascularization, cognitive functions and 123I-IMZ uptake tended to ameliorate (MMSE: 27.5 ± 1.7, FAB: 16.3 ± 2.2, IMZ-ACR: 0.94 ± 0.09). Preoperative cognitive function was associated with 123I-IMZ uptake in adult patients with MMD. After revascularization, cognitive function could be recovered in the viable areas of the brain, which is consistent with 123I-IMZ SPECT findings.

Role of Oxidative Stress in the Occurrence and Development of Cognitive Dysfunction in Patients with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) causes recurrent apnea and intermittent hypoxia at night, leading to several complications such as cognitive dysfunction. However, the molecular mechanisms underlying cognitive dysfunction in OSAS are unclear, and oxidative stress mediated by intermittent hypoxia is an important mechanism. In addition, the improvement of cognitive dysfunction in patients with OSAS varies by different treatment regimens; among them, continuous positive airway pressure therapy (CPAP) is mostly recognized for improving cognitive dysfunction. In this review, we discuss the potential mechanisms of oxidative stress in OSAS, the common factors of affecting oxidative stress and the Links between oxidative stress and inflammation in OSAS, focusing on the potential links between oxidative stress and cognitive dysfunction in OSAS and the potential therapies for neurocognitive dysfunction in patients with OSAS mediated by oxidative stress. Therefore, further analysis on the relationship between oxidative stress and cognitive dysfunction in patients with OSAS will help to clarify the etiology and discover new treatment options, which will be of great significance for early clinical intervention.

Multifunctional Gomisin B enhances cognitive function in APP/PS1 transgenic mice by regulating Aβ clearance and neuronal apoptosis

This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of β-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients.

Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress

Reelin, an extracellular matrix protein with putative antidepressant-like properties, becomes dysregulated by chronic stress. Improvement in cognitive dysfunction and depression-like behavior induced by chronic stress has been reported with both intrahippocampal and intravenous Reelin treatment but the mechanisms responsible are not clear. To determine if treatment with Reelin modifies chronic stress-induced dysfunction in immune organs and whether this relates to behavioral and/or neurochemical outcomes, spleens were collected from both male (n = 62) and female (n = 53) rats treated with daily corticosterone injections for three weeks that received Reelin or vehicle. Reelin was intravenously administered once on the final day of chronic stress, or repeatedly, with weekly treatments throughout chronic stress. Behavior was assessed during the forced swim test and the object-in-place test. Chronic corticosterone caused significant atrophy of the spleen white pulp, but treatment with a single shot of Reelin restored white pulp in both males and females. Repeated Reelin injections also resolved atrophy in females. Correlations were observed between recovery of white pulp atrophy and recovery of behavioral deficits and expression of both Reelin and glutamate receptor 1 in the hippocampus, supporting a role of the peripheral immune system in the recovery of chronic stress-induced behaviors following treatment with Reelin. Our data adds to research indicating Reelin could be a valuable therapeutic target for chronic stress-related disorders including major depression.

Biomarkers related to cognitive dysfunction in APP/PS1 mice based on non-targeted metabonomics and intervention mechanism of Huanglian Jiedu Decoction

Through the non-targeted metabonomics study on endogenous substances in APP/PS1 transgenic mice, this paper aimed to discover biomarkers related to APP/PS1 mice with cognitive dysfunction, and find targets of Huanglian Jiedu Decoction(HLJDD) in the treatment of Alzheimer's disease(AD) and its mechanism. The brain tissue and serum metabolic mass spectrometry of mice were analyzed by ultra-high performance liquid chromatography-Orbitrap mass spectrometry(UPLC-Orbitrap MS). Through partial least squares-discriminant analysis(PLS-DA) and orthogonal partial least squares-discriminant analysis(OPLS-DA), the metabolic data of the normal group, the model group, the high-dose and low-dose HLJDD groups, and the berberine group were compared and analyzed to screen out potential biomarkers, and the relevant metabolic pathways were constructed with the help of the Kyoto Encyclopedia of Genes and Genomes(KEGG) database. Forty-five potential endogenous metabolites were identified, including 13 in brain and 35 in serum, among which leukotriene B4, tyrosine, and adenosine were expected to be differential metabolites related to cognitive function. HLJDD recalled 22 differential metabolites, and the pathways mainly involved in aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, pantothenic acid and coenzyme A biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, and arachidonic acid metabolism. These pathways suggested that the main mechanism of HLJDD in the intervention of AD was to inhibit central and peripheral inflammation, and regulate energy metabolism, fatty acid metabolism, and amino acid metabolism. HLJDD has a certain effect on the improvement of cognitive dysfunction, and regulates relative pathways by recalling endogenous differential metabolites, which helps to further discover the biomarkers of AD and clarify the intervention mechanism of HLJDD in the treatment of AD.

Improvement of cognitive dysfunction by a novel phosphodiesterase type 5 inhibitor, Tadalafil.

There is substantial evidence for the modulatory role of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterases (PDEs) in memory and synaptic plasticity, and an increase in intracellular cGMP facilitates these processes. The present study was aimed at the neuropharmacological investigations of tadalafil (TAD 5, 10, and 20 mg/kg, p.o.) and further involvement of nitric oxide (NO)-cGMP in its effects. The effects of tadalafil and its combination with NG -nitro-L-arginine methyl ester (L-NAME) were investigated in scopolamine- and diabetes-induced cognitive dysfunction using elevated plus maze (EPM) and object recognition (ORT) tests. The results of EPM revealed that the scopolamine- and diabetes-induced learning and memory deficit was dose dependently attenuated after administration of TAD (TAD 10 and 20 mg/kg, p.o.) in both paradigms studied. Administration of L-NAME (20 mg/kg) aggravated scopolamine- and diabetes-induced learning and memory deficit. Co-administration of L-NAME (20 mg/kg) after TAD (20 mg/kg) produced significant increase in cognitive performance as compared to scopolamine- and diabetic- control group. This showed that L-NAME (20 mg/kg) aggravated scopolamine- and diabetes-induced learning and memory deficit was significantly reversed by TAD (20 mg/kg). The results of the present study revealed that tadalafil by inhibiting PDE5 possibly elevated the cGMP level that through a diversity of its substrates produced neuropharmacological effects in cognitive dysfunction.

Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature.

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its clinical potential in the treatment of cognitive impairment in diseases such as Alzheimer's disease (AD) and Parkinson disease (PD) is currently being explored. This review focused on the reported beneficial effects of pioglitazone on cognitive dysfunction and summarized the associated mechanisms associated with pioglitazone-induced improvement in cognitive dysfunction. Our review of the relevant literature indicated that there is conclusive evidence of the effect of pioglitazone on improving cognitive impairment via its agonistic effect on PPAR-γ. Further, several mechanisms of action have been reported, and these include enhanced NF-kB and p38 activity; regulation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α; inhibition of Aβ production; alterations in the levels of mitochondrial proteins such as mitoNEET; regulation of protein kinases such as CDK5 and JNK; regulation of ROS and MDA levels and the levels of the antioxidant proteins TRX1 and PON2; and increased expression of thyroid hormone receptors. Despite these promising findings, pioglitazone treatment is also associated with cardiovascular risks, such as weight gain and edema, which subsequently increase the risk of mortality. Further, it has been documented that pioglitazone may be unable to cross the blood–brain barrier when administered in certain forms, and it can also cause cell death when administered at high concentrations. Therefore, further research is required to explore the effects of acute and chronic pioglitazone treatment on memory function and the associated risks, in order to determine its clinical applicability in the treatment of cognitive disorders. Nonetheless, the current literature does demonstrate that pioglitazone promotes the function of PPAR receptors in ameliorating inflammation, oxidative stress, amyloidogenesis, and hypothyroidism, and enhancing neurogenesis, synaptic plasticity, and mitochondrial function. Therefore, these mechanisms of PPAR receptors warrant further investigation in order to establish the clinical applicability of pioglitazone in the treatment of cognitive disorders, such as PD and AD, and neuronal impairment in conditions such as diabetes.

Suppression of phosphodiesterase IV enzyme by roflumilast ameliorates cognitive dysfunction in aged rats after sevoflurane anaesthesia via PKA-CREB and MEK/ERK pathways.

Postoperative cognitive dysfunction (POCD) is a prevalent disorder after anaesthesia in the elderly patients. Roflumilast (RF), a phosphodiesterase 4 (PDE-4) inhibitor, could improve cognition with no side effects. Here, we sought to explore the efficacy of RF in the improvement of cognitive dysfunction caused by sevoflurane (Sev). Sprague-Dawley rats were anaesthetized, and the hippocampal neurons were treated with Sev to develop in vivo and in vitro POCD models, followed by RF administration. The mechanism of the PKA-CREB and MEK/ERK pathways in the pathogenesis of POCD was explored. Sev impaired the cognitive functions of rats, significantly reduced cyclic adenosine monophosphate (cAMP) concentrations and blocked the PKA-CREB and MEK/ERK pathways. Moreover, the Sev-treated rats and neurons exhibited enhanced apoptosis and reactive oxygen species (ROS). After treatment with RF, rats had better learning and memory function, and the activity of neurons in hippocampus and cortex was improved. Loss-of-function assay indicated that PKA-CREB and MEK/ERK signalling impairment reduced cAMP levels and promoted apoptosis and ROS in rat hippocampus and neurons. Generally, RF promotes neuronal activity in rats after Sev treatment by maintaining cAMP levels and sustaining the activation of PKA-CREB and MEK/ERK pathways. This might offer novel sights for POCD therapy.

Far infrared light irradiation enhances Aβ clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimer’s disease-like mice

BackgroundExposure to sunlight may decrease the risk of developing Alzheimer’s disease (AD), and visible and near infrared light have been proposed as a possible therapeutic strategy for AD. Here, we investigated the effects of the visible, near infrared and far infrared (FIR) light on the cognitive ability of AD mice, and found that FIR light also showed potential in the improvement of cognitive dysfunction in AD. However, the related mechanism remains to be elucidated.MethodsMorris water maze was used to evaluate the cognitive ability of APPswe/PSEN1dE9 double-transgenic AD mice after light treatment. Western blot was carried out to detect the expression of protein involved in synaptic function and amyloid-β (Aβ) production. The protein amount of interleukin (IL)-1β, IL-6, Aβ1-40 and Aβ1-42 were determined using enzyme-linked immunosorbent assay. The mRNA level of receptors was performed using real-time quantitative polymerase chain reaction. Immunostaining was performed to characterize the Aβ burden and microglial Aβ phagocytosis in the brain of AD mice. The Aβ phagocytosis of primary cultured microglia and BV2 were assessed by flow cytometry. The energy metabolism changes were evaluated using related assay kits, including adenosine triphosphate (ATP), lactate content, mitochondrial respiratory chain complex enzymatic activity and oxidized/reduced nicotinamide adenine dinucleotide assay kits.ResultsOur results showed that FIR light reduced Aβ burden, a hallmark of AD neuropathology, alleviated neuroinflammation, restored the expression of the presynaptic protein synaptophysin, and ameliorated learning and memory impairment in the AD mice. FIR light enhanced mitochondrial oxidative phosphorylation pathway to increase ATP production. This increased intracellular ATP promoted the extracellular ATP release from microglia stimulated by Aβ, leading to the enhanced Aβ phagocytosis through phosphoinositide 3-kinase/mammalian target of rapamycin pathways for Aβ clearance.ConclusionsOur findings have uncovered a previously unappreciated function of FIR light in inducing microglial phagocytosis to clean Aβ, which may be the mechanisms for FIR light to improve cognitive dysfunction in AD mice. These results suggest that FIR light treatment is a potential therapeutic strategy for AD.

Improvement of cognitive function, glucose and lipid homeostasis and serum osteocalcin levels by liraglutide in diabetic rats.

Glucose and lipid abnormalities, oxidative stress (OXS) and reduced brain-derived neurotrophic factor (BDNF) are involved in cognitive dysfunction in diabetes. Glucagon like peptide 1 (GLP1) receptors modulate glucose and lipid metabolism, cognitive function and serum osteocalcin. On the other hand, osteocalcin modulates cognitive function and glucose and lipid metabolism. This study investigated whether the GLP 1 agonist liraglutide improves cognitive function via modulation of serum osteocalcin and glucose and lipid metabolism. Effects of 4weeks liraglutide treatment (100µg/Kg/d and 300µg/Kg/d) on changes in cognitive function and bone homeostasis, induced by high fat diet/low-dose streptozotocin (HFD-STZ), were determined in rats. Cognitive function was assessed using Morris water maze (MWM) test. Serum and bone biochemical parameters were determined. Liraglutide dose-dependently improved cognitive function in diabetic rats (reduced escape latency, and increased time spent in target quadrant in MWM test, compared to diabetic control). Glucose and lipid abnormalities and the associated changes in serum BDNF and oxidative stress makers were improved. Serum BDNF and glutathione were significantly increased, whereas malondialdehyde level was reduced. Serum osteocalcin was significantly increased and correlated with improvement in cognitive dysfunction. Serum and bone receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin ratios were significantly reduced by liraglutide treatment. Improvement of cognitive dysfunction by liraglutide involves modulation of glucose and lipid metabolism and serum osteocalcin. GLP1 agonists may provide an alternative metabolic approach for cognitive dysfunction in diabetes.

Improvement in cognitive dysfunction following blast induced traumatic brain injury by thymosin α1 in rats: Involvement of inhibition of tau phosphorylation at the Thr205 epitope

Cognitive impairment is a significant sequela of traumatic brain injury (TBI) especially blast induced traumatic brain injury (bTBI), which is characterized by rapid impairments of learning and memory ability. Although several neuroprotective agents have been postulated as promising drugs for bTBI in animal studies, very few ideal therapeutic options exist to improve cognitive impairment following bTBI. Thymosin α1(Tα1), a 28-amino-acid protein that possesses immunomodulatory functions, has exhibited beneficial effects in the treatment of infectious diseases, immunodeficiency diseases and cancers. However, it remains unclear whether Tα1 has a therapeutic role in bTBI. Thus, we hypothesized that Tα1 administration could reverse the outcomes of bTBI. The blast induced TBI (bTBI) rat model was established with the compressed gas driven blast injury model system. A consecutive Tα1 therapy (in 1 ml saline, twice a day) at a dose of 200 µg/kg or normal saline (NS) (1 ml, twice a day) for 3 days or 2 weeks was performed. Utilizing our newly designed bTBI model, we investigated the beneficial effects of Tα1 therapy on rats exposed to bTBI including: cognitive functions, general histology, regulatory T (Treg) cells, edema, inflammation reactions and the expression and phosphorylation level of tau via Morris Water Maze test (MWM test), HE staining, flow cytometry, brain water content (BWC) calculation, IL-6 assay and Western blotting, respectively. Tα1 treatment seemed to reduce the 24-hour mortality, albeit with no statistical significance. Moreover, Tα1 treatment markedly improved cognitive dysfunction by decreasing the escape latency in the acquisition phase, and increasing the crossing numbers in the probe phase of MWM test. More interestingly, Tα1 significantly inhibited tau phosphorylation at the Thr205 epitope, but not at the Ser404 and Ser262 epitopes. Tα1 increased the percentage of Treg cells and inhibited plasma IL-6 production on 3d post bTBI. Moreover, Tα1 suppressed brain edema as demonstrated by decrease of BWC. However, there was a lack of obvious change in histopathology in the brain upon Tα1 treatment. This is the first study showing that Tα1 improves neurological deficits after bTBI in rats, which is potentially related to the inhibition of tau phosphorylation at the Thr205 epitope, increased Treg cells and decreased inflammatory reactions and brain edema.

Liver-related effects of chronic hepatitis C antiviral treatment.

More than five years ago, the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral (DAA) drugs. They proved highly efficient in curing patients with chronic hepatitis C (CHC), including patients with cirrhosis. The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis, but the exact cause of the expected benefit was unclear. Further, little was known about how the underlying liver disease would be affected during and after viral clearance. In this review, we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects, such as macrophage activation, and the time-dependent effects of therapy, with specific emphasis on inflammation, structural liver changes, and liver function, as these factors are all related to morbidity and mortality in CHC patients. It seems clear that antiviral therapy, especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis. There seems to be a time-dependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions. These improvements lead to favorable effects on liver function, followed by an improvement in cognitive dysfunction and portal hypertension. Overall, the data provide knowledge on the several beneficial effects of DAA therapy on liver-related parameters in CHC patients suggesting short- and long-term improvements in the underlying disease with the promise of an improved long-term prognosis.

Liver Transplant Is Associated with Sustained Improvement in Tandem Gait and Risk of Falls.

Cirrhosis is associated with poor health-related quality of life (HRQOL), cognitive dysfunction (CD), and lack of coordination leading to falls. Tandem gait (TG; heel-toe) can be used to assess coordination. The impact and relationship between CD, TG and falls pre-/post-liver transplant (LT) is unclear. We aimed to determine the impact of LT on CD, abnormal TG, and HRQOL in cirrhosis. We analyzed patients who underwent complete neurological examination, cognitive testing by psychometric hepatic encephalopathy score (PHES), and HRQOL assessment using sickness impact profile (SIP). All patients were followed for 1 post-LT visit at 6 or 12months post-LT for clinical course and falls. Change in CD, TD, and falls pre-/post-LT were compared. Off 131 recruited, 61 patients completed all visits. Majority were men (84%), with HCV etiology (34%). Pre-LT: Abnormal TG trended towards increased falls (OR 3.3, P = 0.08). Forty-nine % had abnormal TG, 61% had CD, 32.7% had CD + abnormal TG, 62% had prior OHE, and 14.7% had falls. Abnormal and normal TG patients had similar ages, BMI, sex, education level, and MELD scores. Abnormal TG group had higher prior overt HE (P = 0.03) and worse physical SIP score (P = 0.008). Post-LT: There was sustained improvement in CD, HRQOL, falls, and TG post-LT more at 12 than 6months in all patients. Patients who had abnormal TG pre-LT continued to have a worse PHES (P = 0.0064) and physical SIP score (P = 0.008) compared to normal pre-LT TG patients. After LT, there is a sustained improvement in coordination measured via tandem gait, accompanied by a lower rate of falls.

Metformin therapy and cognitive dysfunction in patients with type 2 diabetes: A meta-analysis and systematic review.

Background:Type 2 diabetes (T2D) is a risk factor for cognitive dysfunction. The relationship between metformin therapy and cognitive function in patients with T2D is unknown. Therefore, we determined the relationship between metformin therapy and cognitive function in patients with T2D using a meta-analysis.Methods:We systematically searched the Cochrane library, PubMed, and Embase to identify studies showing correlations, and we calculated hazard ratios (HRs).Results:We identified 10 studies including 254,679 participants. Metformin significantly reduced the occurrence of cognitive dysfunction in patients with T2D (HR 0.90; 95% CI [0.88, 0.92]). Compared with other hypoglycemic drugs, sulfonylureas also improved cognitive dysfunction (HR 0.92; 95% CI [0.88, 0.95]). Thiazolidinediones gave no statistically significant improvement in cognitive dysfunction (HR 0.97; 95% CI [0.87, 1.07]). The use of insulin aggravated cognitive dysfunction (HR 1.34; 95% CI [1.24, 1.43]). In the subgroup analysis of various regions controlling for age, gender, education, diabetes course, complications, metformin administration and dosage, and follow-up time, metformin significantly improved cognitive dysfunction in patients in the Americas and Europe (HR 0.69; 95% CI [0.63, 0.74]), (HR 0.71; 95% CI [0.66, 0.76], respectively), while metformin did not significantly improve cognitive dysfunction in Asian patients (HR 0.99; 95% CI [0.96, 1.01]).Conclusions:Metformin significantly improved cognitive dysfunction in patients with T2D. Sulfonylureas also improved cognitive dysfunction. Thiazolidinediones had no significant effect on cognitive dysfunction. The use of insulin aggravated cognitive dysfunction. Metformin improved cognitive dysfunction more significantly in patients in the Americas and Europe than in Asia.

Activation of Astroglial Connexin is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine.

Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis.

Assessment of current clinical practices for major depression in Japan using a web-based questionnaire.

PurposeTo investigate the current clinical practice of Japanese physicians in the diagnosis and management of major depression (major depressive disorder [MDD]).Patients and methodsJapanese physicians specializing in psychiatry or psychosomatic medicine in the medical database of Nihon Ultmarc Inc. (Chuo-Ku, Tokyo, Japan), who had treated ≥30 patients with MDD in the past month were invited to complete a web-based questionnaire from January 15 to 29, 2018. The questionnaire was comprised of 28 questions pertaining to the physician’s background, the criteria and tools used to diagnose MDD during physician–patient consultation, and actual and preferred duration of physician–patient consultation. Responses were given as single answer numerical values or as multiple-choice answers.ResultsFrom the 518 physicians invited to participate, 340 completed questionnaires were analyzed. Respondents were predominantly male (90%), hospital based (73%), affiliated with the Department of Psychiatry (95%), and members of the Japanese Society of Psychiatry and Neurology (87%). The majority of physicians (84%) agreed that “improvement of cognitive dysfunction caused by major depression is an important factor for patients to return to work” was the most challenging aspect of MDD diagnosis and management. Moreover, 83% of physicians conducted psychological assessments using a cognition evaluation test with most of their patients at the time of MDD diagnosis; the most commonly used tool was the Hasegawa Dementia Scale-Revised. Both hospital-based physicians and general practitioners would prefer to have longer consultations with their patients.ConclusionPhysicians acknowledge the importance of the assessment and management of cognitive dysfunction in patients with MDD. However, most physicians would prefer to have longer consultation times with their patients for the diagnosis of MDD. In the future, it may be useful to introduce digital tools (eg, THINC-it®) for the initial screening of cognitive dysfunction.

Neuroprotective Properties of the Standardized Extract from Camellia sinensis (Green Tea) and Its Main Bioactive Components, Epicatechin and Epigallocatechin Gallate, in the 6-OHDA Model of Parkinson's Disease.

Camellia sinensis (green tea) is largely consumed, mainly in Asia. It possesses several biological effects such as antioxidant and anti-inflammatory properties. The objectives were to investigate the neuroprotective actions of the standardized extract (CS), epicatechin (EC) and epigallocatechin gallate (EGCG), on a model of Parkinson's disease. Male Wistar rats were divided into SO (sham-operated controls), untreated 6-OHDA-lesioned and 6-OHDA-lesioned treated for 2 weeks with CS (25, 50, or 100 mg/kg), EC (10 mg/kg), or EGCG (10 mg/kg) groups. One hour after the last administration, animals were submitted to behavioral tests and euthanized and their striata and hippocampi were dissected for neurochemical (DA, DOPAC, and HVA) and antioxidant activity determinations, as well as immunohistochemistry evaluations (TH, COX-2, and iNOS). The results showed that CS and catechins reverted behavioral changes, indicating neuroprotection manifested as decreased rotational behavior, increased locomotor activity, antidepressive effects, and improvement of cognitive dysfunction, as compared to the untreated 6-OHDA-lesioned group. Besides, CS, EP, and EGCG reversed the striatal oxidative stress and immunohistochemistry alterations. These results show that the neuroprotective effects of CS and its catechins are probably and in great part due to its powerful antioxidant and anti-inflammatory properties, pointing out their potential for the prevention and treatment of PD.

P.2.f.013 Clinical evidence for improvement in cognitive dysfunction in patients with major depressive disorder (MDD) after treatment with vortioxetine

P.2.f.013 Clinical evidence for improvement in cognitive dysfunction in patients with major depressive disorder (MDD) after treatment with vortioxetine

Pharmacological Aspects of the Acetylcholinesterase Inhibitor Galantamine

Several lines of evidence suggest that cholinergic deficits may contribute to the pathophysiology of psychiatric disorders as well as Alzheimer's disease. There is growing clinical evidence that galantamine, currently used for the treatment of Alzheimer's disease, may improve cognitive dysfunction and psychiatric illness in schizophrenia, major depression, bipolar disorder, and alcohol abuse. Since galantamine is a rather weak acetylcholinesterase inhibitor, but has additional allosteric potentiating effects at nicotinic receptors, it affects not only cholinergic transmission but also other neurotransmitter systems such as monoamines, glutamate, and γ-aminobutyric acid (GABA) through its allosteric mechanism. It is likely that these effects may result in more beneficial effects. To understand the underlying mechanism for the clinical effectiveness of galantamine, neuropharmacological studies have been performed in animal models of several psychiatric disorders. These studies suggest that not only the nicotinic receptor-modulating properties but also the muscarinic receptor activation contribute to the antipsychotic effect and improvement of cognitive dysfunction by galantamine. This review summaries the current status on the pharmacology of galantamine, focusing on its effect on neurotransmitter release and pharmacological studies in animal models of psychiatric disorders.