Improvement Of Cognitive Deficits Research Articles

Exploring animal protein sources against prevent age-related short-term memory decline in mice: Dietary fish (Alaska Pollock) protein exhibits superior protective effects.

Dietary factors, particularly proteins, have been extensively explored to combat cognitive impairment. We have previously reported that dietary fish (Alaska Pollock) protein (APP) is more effective than casein (CAS) or fish oil in maintaining short-term memory in senescence-accelerated mice prone 10 (SAMP10). To examine the specificity of the protective effect of APP intakes against short-term memory decline, we assessed the impact of various dietary animal proteins, including APP, CAS, chicken breast protein (CP), and whey protein (WP), against age-related cognitive function in SAMP10 mice. After feeding the experimental diets for 5 months, memory was assessed using the Y-maze. The APP group exhibited a significant increase in spontaneous alternation behavior as an indicator of working memory when group compared with groups fed with other protein source. Additionally, the APP group displayed significantly higher neurofilament heavy chain positivity than the CAS and CP groups, as evidenced immunohistochemical analysis. Gut microbiota analysis indicated that dietary APP significantly enhanced the relative abundance of Lactobacillus, which positively correlated with spontaneous alternation behavior. Collectively, these findings suggest that dietary APP is more effective than CAS, CP, or WP in preventing age-related short-term memory decline and morphological abnormalities in the hippocampal axons of SAMP10 mice. Moreover, APP-mediated improvements in cognitive deficits may be associated with changes in microbiota diversity. PRACTICAL APPLICATION: This research suggests that dietary fish protein from Alaska Pollock may be more efficient in prevention short-term memory decline in mice, compared to other animal proteins. This finding has practical implications for nutritional optimization, developing the new health food products, and elucidating the relationship between the impact of specific proteins on gut microbiota and prevention of age-related cognitive decline.

Impacts of metabolic disruption, body mass index and inflammation on cognitive function in post-COVID-19 condition: a randomized controlled trial on vortioxetine

BackgroundPost-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI.MethodsThis is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5–20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint.ResultsOur findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047).ConclusionOverall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo.Trial RegistrationNCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021).

Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings

BackgroundNumerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. MethodsWe conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. ResultsThe meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. ConclusionsOur findings support the “IGF-1 deficiency hypothesis” in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.

Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.

Background: The impediment to β-amyloid (Aβ) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aβ from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.

Effects of Levothyroxine on Behavior and Cognitive Decline in a Rat Model of Multiple Sclerosis: A Biochemical Study

Background: Multiple sclerosis (MS) is an autoimmune disease in the central nervous system (CNS) that affects the development and physiological function of the brain and causes memory impairment. Objectives: Due to the anti-inflammatory and antioxidant role of levothyroxine (L-T4) on myelin production and adult cerebral function, this study aimed to evaluate the effects of L-T4 on the improvement of cognitive deficits and cerebral inflammation. Methods: Forty Wistar rats were randomly divided into five groups: (1) sham, (2) L-T4, (3) MS, (4) MS receiving L-T4, and (5) Betaferon. For MS induction, lysolecithin was injected into the CA1 of the hippocampus. Rats received L-T4 intraperitoneally at a dose of 100 μg/kg in the second and fourth groups. The shuttle box and Morris water maze tests were used to investigate passive avoidance and spatial memory, respectively. Also, the hippocampal concentrations of total antioxidant capacity (TAC), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and c-reactive protein (CRP) were measured to investigate molecular changes. Results: Path length (P < 0.001, P = 0.0015, and P = 0.002 on days 1 to 3, respectively) and latency time (P < 0.001 on the second and third days) increased, but the speed of movements (P < 0.001) and time spent in goal quarter decreased in MS-induced groups (P < 0.001). Treatment with L-T4 for 14 days significantly reversed path length and speed (P < 0.001 and P = 0.0315 on the second and third days), latency time (P < 0.01), speed (P < 0.001 and P = 0.0038 on the second and third days), and time spent in goal quarter (P = 0.1203) in the MS group. The hippocampal concentrations of MDA (P = 0.0010), TNF-α (P = 0.0251), and CRP (P = 0.0065) were significantly lower in the MS group treated with L-T4 than in the MS group. Also, the hippocampal concentration of TAC was significantly increased (P = 0.0375) in the MS group receiving L-T4. Conclusions: It seems that treatment with L-T4 can prevent cognitive impairment caused by MS induction. Ameliorative effects of L-T4 may be due to the reduction of inflammation and oxidative stress. Therefore, L-T4 can be used as an effective agent in the treatment of MS.

Peripheral Administration of the Kv1.3-Blocking Peptide HsTX1[R14A] Improves Cognitive Performance in Senescence Accelerated SAMP8 Mice

Increased expression of the voltage-gated potassium channel Kv1.3 in activated microglia, and the subsequent release of pro-inflammatory mediators, are closely associated with the progression of Alzheimer’s disease (AD). Studies have shown that reducing neuroinflammation through the non-selective blockade of microglial Kv1.3 has the potential to improve cognitive function in mouse models of familial AD. We have previously demonstrated that a potent and highly-selective peptide blocker of Kv1.3, HsTX1[R14A], not only entered the brain parenchyma after peripheral administration in a lipopolysaccharide (LPS)-induced mouse model of inflammation, but also significantly reduced pro-inflammatory mediator release from activated microglia. In this study, we show that microglial expression of Kv1.3 is increased in senescence accelerated mice (SAMP8), an animal model of sporadic AD, and that subcutaneous dosing of HsTX1[R14A] (1 mg/kg) every other day for 8 weeks provided a robust improvement in cognitive deficits in SAMP8 mice. The effect of HsTX1[R14A] on the whole brain was assessed using transcriptomics, which revealed that the expression of genes associated with inflammation, neuron differentiation, synapse function, learning and memory were altered by HsTX1[R14A] treatment. Further study is required to investigate whether these changes are downstream effects of microglial Kv1.3 blockade or a result of alternative mechanisms, including any potential effect of Kv1.3 blockade on other brain cell types. Nonetheless, these results collectively demonstrate the cognitive benefits of Kv1.3 blockade with HsTX1[R14A] in a mouse model of sporadic AD, demonstrating its potential as a therapeutic candidate for this neurodegenerative disease.

Evaluations of the neuroprotective effects of a dual-target isoquinoline inhibitor in the triple transgenic mouse model of Alzheimer's disease

Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (Aβ) plaques and neurogenic fibrillary tangles. These features are thought to play important pathogenic roles, including neuronal dysfunction and apoptosis in the disease progression. Herein, we systematically evaluated a previously reported dual-target isoquinoline inhibitor (9S) for cholinesterase and Aβ aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in Aβ-induced and PHF6-induced PC12 cell models as well as in an okadaic acid-induced SH-SY5Y cell model, which were due to attenuated neuronal apoptosis through modulations of GSK-3β phosphorylation and reactive oxygen species. One-month administration of 9S to triple transgenic AD (3 × Tg-AD) female mice (aged 6 months) led to significant improvement in cognitive deficits. Whereas similar treatment regimens for older 3 × Tg-AD female mice (aged 10 months) showed negligible neuroprotective effects. These findings suggest the importance of therapeutic intervention at the early stage of the disease.

Berberine hydrochloride improves cognitive deficiency through hippocampal up-regulation of neurotrophins following inhalant self-administration of methamphetamine.

Chronic methamphetamine (METH) abuse is recognized as an important risk factor for cognitive impairment. A plant-based isoquinoline alkaloid, Berberine hydrochloride (BER), shows memory and cognition enhancement properties. Due to the aim of the present study which is to investigate the influence of BER administration on METH-induced cognitive deficits, we investigated neurotrophin signaling including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) as a possible mechanism by which BER exerts its cognitive improvement influences. In this experimental study, thirty-two male Wistar rats were randomly classified into four groups, including non-treated control, intubated control, METH-inhaled, and METH-inhaled + BER-intubated. Rats in the METH-inhaled group underwent METH inhalation for 14 days, and the BER-inhaled and BER-intubated rats were intubated (100mg/kg) for the following three weeks. A novel object recognition task (NORt) was carried out on days 36 and 37. Rats were sacrificed for histological preparations after the behavioral tests. Neurotrophic factors, including GDNF and BDNF, were evaluated by immunofluorescence staining in the hippocampus. This experiment indicated a dramatic improvement in cognitive deficits associated with chronic METH abuse (P<0.001). Furthermore, a significant decrease in the expression of both neurotrophins, GDNF (P<0.001) and BDNF (P<0.001), was observed in the METH-inhaled group compared with the METH-inhaled group treated with BER and non-treated control group. Activation of neurotrophic factors after BER administration resulted in improvement of METH-induced cognitive deficits. Therefore, BER may be considered a promising treatment for METH users who experience cognition deficits.

Fingolimod ameliorates schizophrenia-like cognitive impairments induced by phencyclidine in male rats.

Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway. This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.

Resveratrol reduces inflammatory response and detrimental effects in chronic cerebral hypoperfusion by down-regulating stimulator of interferon genes/TANK-binding kinase 1/interferon regulatory factor 3 signaling.

Inflammatory responses induced by chronic cerebral hypoperfusion (CCH) play a critical role in the progression of vascular dementia. Stimulator of interferon genes (STING) signaling function as a key mediator of inflammation and immunological responses in the central nervous system (CNS), and resveratrol (RES) exerts potent anti-inflammatory effects. However, the role of STING signaling and the relationship between RES and STING signaling in persistent hypoperfusion-induced cerebral inflammation remain unclear. In this study, Sprague–Dawley rats were subjected to either Sham or bilateral common carotid artery occlusion (2VO) surgery and received RES or vehicle daily by intraperitoneal injection for 4 or 8 weeks. Morris’s water maze was used for the analysis of cognitive function. The neuroinflammatory responses in white matter and hippocampus of the rat brain were assessed by Western blot, Immunofluorescence staining, and qRT-PCR analyses. Myelin integrity, neutrophil infiltration, and microglia proliferation were assessed by Immunohistochemistry and histologic analysis. We demonstrated that after CCH, neurons, microglia, and astrocyte under endoplasmic reticulum (ER) stress upregulated the expression of STING, TANK-binding kinase 1 (TBK1), and the transcription factor interferon regulatory factor 3 (IRF3), as well as translocation of IRF3 into the nucleus. These were accompanied by infiltration of neutrophils, activation of microglia, and overproduction of proinflammatory mediators. Improvements in cognitive deficits were related to reduced hippocampal neuronal cell death and increased myelin integrity in RES-treated rats. The neuroprotective effects of RES were associated with suppression of the expression of tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), VCAM-1, interferon-β (IFN-β), and IL-1β, likely through mitigation of the STING/TBK1/IRF3 pathway. These inhibitory effects exerted by RES also inhibited the levels of myeloperoxidase, reduced excess expression of reactive astrocytes, and activated microglia. In conclusion, the STING/TBK1/IRF3 axis may be critical for proinflammatory responses in cerebral tissue with persistent hypoperfusion, and RES exerts its anti-inflammatory effects by suppressing STING/TBK1/IRF3 signaling.

Adipose tissue-derived stem cells as a potential candidate in treatment of Alzheimer's disease: A systematic review on preclinical studies.

In recent years, numerous investigations have evaluated the efficacy of adipose tissue‐derived stem cells (ADSCs) and their exosome transplantation in managing Alzheimer's disease (AD) in different animal models. However, there are still many contradictions among the studies that hinder reaching a reliable conclusion. Therefore, we aimed to systematically review the existing evidence regarding the efficacy of ADSCs administration in treatment of AD. The systematic search was conducted in the databases of Medline (via PubMed), Embase, Scopus, and Web of Science, in addition to the manual search in Google and Google scholar, to find articles published until March 13, 2021. Preclinical studies were included and two independent reviewers summarized the eligible papers. Ten articles were included in our review. The treatment strategies varied between isolated ADSC, ADSCs exosomes, ADSCs conditioned medium, and combination therapy (ADSCs plus conditioned medium in one study, and ADSCs plus melatonin in another study). Overview of the included articles showed promising results of ADSCs and its conditioned medium/exosome administration in animal models of AD. These studies showed significant learning and memory improvements through ADSCs and their conditioned medium/exosome administration in animal models of AD. In addition, the application of ADSCs reduced the amyloid‐beta plaque deposits in the hippocampus and neocortex of these animals. Based on the aforementioned evidence, studies have suggested potential beneficial effects of ADSCs in the treatment of AD, particularly through decreasing the size of Aβ plaques and improvement of cognitive deficits. Further investigations regarding the subject are encouraged to achieve more accurate conclusions.

Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer's Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress.

Alzheimer's disease is identified by pathological hallmarks such as intracellular neurofibrillary tangles (NFTs) and extracellular amyloid β plaques. Several hypotheses exist to define the neurodegeneration including microglial activation associated with neuroinflammatory processes. Recently, pharmacological inhibition of endocannabinoid (eCB)-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), is being investigated to modulate the pathology of Alzheimer's disease. While MAGL inhibitors upregulate 2-acyl glycerol (2-AG) levels and reduce neuroinflammation, FAAH inhibitors elevate anandamide (AEA) levels and prevent the degradation of HSP-70, thereby preventing the phosphorylation of tau protein and formation of NFTs in neural cells. We investigated the possible neuroprotective potential of the dual MAGL/FAAH inhibitor JZL-195 (20 mg/kg) against ICV-STZ-induced sporadic Alzheimer's disease (SAD) in Swiss albino mice using donepezil (5 mg/kg) as the standard. The protective effects of JZL-195 were observed by the reversal of altered levels of Aβ1-42, HSP-70, neuroinflammatory cytokines, and oxidative stress markers. However, JZL-195 expressed no cognitive improvement when assessed by spontaneous alternation behavior and Morris water maze tests and no effects on the AChE enzyme level in the hippocampal tissues of mice. Therefore, the findings of the present study indicate that although JZL-195 exhibited no improvement in cognitive deficits associated with sporadic Alzheimer's disease, it displayed significant reversal of the biochemical anomalies, thereby suggesting its therapeutic potential against the sporadic Alzheimer's disease model.

Memantine improves cognitive deficits via KATP channel inhibition in olfactory bulbectomized mice

Patients with Alzheimer's disease (AD) demonstrate severely impaired olfactory systems, which occur in the early stages of the disease. Olfactory bulbectomy (OBX) in mice elicits cognitive deficits, and reduces cholinergic activity in the hippocampus. Here, we confirmed that the novel AD drug memantine rescues cognitive deficits via ATP-sensitive potassium (KATP) channel inhibition in OBX mice. Repeated memantine administration at 1–3 mg/kg p.o. for 14 days starting at 10 days after OBX surgery significantly rescued cognitive deficits in OBX mice, as assessed using Y-maze, novel object recognition, and passive avoidance tasks. Consistent with the rescued cognitive deficits in OBX mice, long-term potentiation (LTP) in the hippocampal cornu ammonis (CA) 1 region was markedly restored with memantine administration. As demonstrated by immunoblotting, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) α (Thr-286) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV; Thr-196) phosphorylation in the CA1 region of OBX mice were significantly restored with memantine. Conversely, pre-treatment with pinacidil, a KATP channel opener, failed to reinstate hippocampal LTP and CaMKII/CaMKIV activities in the CA1 region. Finally, improvement of cognitive deficits by memantine treatments was observed in OBX-operated Kir6.1 heterozygous (+/−) mice but not in OBX-operated Kir6.2 heterozygous (+/−) mice. Overall, our study demonstrates that memantine rescues OBX-induced cognitive deficits via Kir6.2 channel inhibition in the CA1 region.

Comparative Efficacy of Active Group Music Intervention versus Group Music Listening in Alzheimer's Disease.

Background: Music interventions are promising therapies for the management of symptoms in Alzheimer’s disease (AD). Globally, music interventions can be classified as active or receptive depending on the participation of the subjects. Active and receptive music tasks engage different brain areas that might result in distinctive clinical effects. This study aims to compare the clinical effects of two types of music interventions and a control activity. Methods: Ninety AD patients from six nursing homes participated in the study. Nursing homes were randomly and blindly assigned to receive either active music intervention, receptive music intervention, or the usual care. Effects on cognition, behaviour, daily living activities, and motor function were assessed. Results: Active music intervention improved cognition, behaviour, and functional state in a higher extent than both receptive music intervention and usual care. The effect size of active music intervention for cognitive deficits and behavioural symptoms was large (η2 = 0.62 and 0.61, respectively), while for functional state, it was small-to-medium sized (η2 = 0.18). Receptive music intervention had a stabilizing effect on behavioural symptoms compared to control intervention (mean change from baseline ± standard deviation = −0.76 ± 3.66 and 3.35 ± 3.29, respectively). In the active music intervention, the percentage of patients who showed improvement in cognitive deficits (85.7), behavioural symptoms (92.9), and functional state (46.4) was higher than in both receptive listening (11.8, 42.9, and 14.3, respectively) and control group (6.3, 12.2, and 17.1, respectively). Conclusions: Active music intervention is useful to improve symptoms of AD and should be prescribed as a complement to the usual treatment.

The improvement of cognitive deficits after whole-body cryotherapy - A randomised controlled trial.

Whole-body cryotherapy (WBC) - a repetitive, short-term exposure to extremely low temperatures - may become an effective early intervention for mild cognitive impairment (MCI). It is a heterogeneous group of symptoms associated with cognitive dysfunction which is estimated to transform into dementia in 50% cases. The prospective randomised double-blind sham-controlled study aimed to determine the efficacy of WBC on cognitive functioning and biological mechanisms. The study was registered with Australian New Zealand Clinical Trials Registry (ACTRN12619001627145). Participants with MCI (n=62; (20<MoCA>26) were randomly allocated to cryogenic temperatures (-110°C till -160°C) (EG, n=33) or placebo-controlled group (CG, n=29). Cognitive functions were measured at baseline (T1), after the 10th WBC session (T2) and after 2week-break (T3) with DemTect, SLUMS and Test Your Memory (TYM). Secondary outcome measures included quality of life (WHOQoL-BREF), self-reported well-being (VAS) and depressive symptoms (GDS). Whole blood samples (10ml) were collected at T1 and T2 to evaluate levels of cytokines, neurotrophins, NO and biochemical parameters CRP total cholesterol, prolactin). There were significant differences between groups measured at T2 in immediate recall (DemTect) and in orientation (TYM) in favour of WBC group. Improvement in mood was detected in self-reported depressive symptoms level (WHOQoL-26; T2 p=0.04; VAS mood T2 p=0.02; T3 p=0.07). The significant reduction of BDNF level was observed (p<0.05). WBC may increase the performance of cognitive functions. It seems promising to combine WBC with existing behavioural and cognitive trainings in the future studies investigating early interventions methods in MCI.

Psychiatric manifestations in a case of viral limbic encephalitis.

Limbic encephalitis (LE), first described by Brierley et al. in 1960,[1] usually involving the medial temporal lobe, cingulate cortex, or hippocampus.[2] The clinical picture includes subacute recent onset of short-term memory loss, cognitive deficits,[3] confusion, seizures, autonomic disturbances, and sleep disturbances.[4] It is a rare cause of encephalitis and may or may not be associated with paraneoplastic cancers. The prognosis of the patient is better if the diagnosis is clinched early and prompt treatment is instituted.[1] Psychiatrists should keep the diagnosis of LE in mind when the patient presents with psychiatric manifestations along with seizures. A 60-year-old male, a known case of diabetes mellitus, hypertension, cerebrovascular accident, seizure disorder with poor drug compliance, and irregular follow-up presented with a history of multiple episodes of generalized tonic-clonic seizures within a span of 3 h. The patient had also developed vesicular lesions over the face on the right side, 3 days before onset of seizures. He was treated with injection levetiracetam 1000 mg for episodes of seizures in Emergency when the call was placed to the psychiatrist to rule out alcohol withdrawal. History revealed that the patient was a moderate drinker for the last 25 years and the last drink consumed was 3 days ago. The patient was asymptomatic till the onset of seizures. Mental status examination revealed an ill-kempt, agitated, restless, confused individual with cognitive deficit. The Glasgow Coma Score (GCS) of the patient deteriorated to5 (E2V1M2) and SPO2 levels fell to 80%. In view of low GCS, not maintaining oxygen saturation levels, the patient was intubated. Hematological investigations, biochemical parameters, serum electrolytes, liver function tests were unremarkable. Cerebrospinal fluid (CSF) analysis revealed lymphocytosis, raised protein, and globulin levels which was suggestive of viral etiology. Noncontrast enhanced computed tomography head showed cerebral edema and ill-defined hypodense lesions in the temporal region. Magnetic resonance imaging (MRI) [Figure 1] T2-weighted and fluid-attenuated inversion recovery revealed hyperintense lesions in medial temporal lobes and cingulate gyrus which were compatible with LE. Based on the suspected facial lesions, investigations suggesting viral etiology, and suboptimal response to treatment, the patient was started on injection acyclovir 600 mg intravenously thrice a day along with antiepileptic medications. The patient was taken off ventilator and sedation was stopped on 4th day. On reassessment, he was found to be aggressive and restless. Mental status examination revealed an ill-kempt, uncooperative individual with increased motor activity with agitation and aggressive behavior. Speech was incoherent, most of the time struggling at high pitch. The patient had fluctuating levels of consciousness and had memory loss. The clinical cognitive evaluation revealed attention to be arousable; however, concentration was ill-sustained. Following antiviral and antiepileptic medications, the patient's mental status improved over the next 2 weeks. However, he had less improvement in cognitive deficits. Over the following 2 weeks, overall gradual improvement was observed and the patient's behavior became less disorganized and became ambulatory.Figure 1: Magnetic resonance imaging showing hyperintense lesions in both medial temporal lobes compatible with limbic gyrusLE shows many symptoms ranging from delusions, confusion, hallucinations, aggression, irritability, memory impairment, and seizure disorders. The medial temporal lobe is the usual site of origin of seizures. It later develops into secondary generalized seizures which are resistive to most of the anti-epileptic drugs.[5] The triggering factors may be paraneoplastic tumors, viral infections, or immune checkpoint inhibitors There are multiple antibodies which are responsible for diverse symptoms present in the patients. Imaging and CSF analysis is required to rule out tumors and viral encephalitis respectively.[6] LE generally presents in individuals over the age of 45 years and gender depends on the type of antibody present.[6] Antibodies associated with LE are initiated by a peripheral immune response.[7] The diagnostic criteria for LE include various neuropsychiatric manifestations, findings of CSF suggestive of ongoing inflammation, and typical abnormality in radio-imaging. Diagnosis is often missed and probably underreported. MRI plays a pivotal role in establishing a diagnosis, where it shows hyper-intensive lesions, usually in the medial part of the temporal lobes. Prompt treatment should be initiated to prevent long-term sequela and to allow a speedy recovery. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Oral benfotiamine reverts cognitive deficit and increase thiamine diphosphate levels in the brain of a rat model of neurodegeneration.

It is well known that patients with Alzheimer's disease (AD) have imbalances in blood thiamine concentrations and lower activity of thiamine-dependent enzymes. Benfotiamine, a more bioavailable thiamine analog, has been proposed as an alternative to counteract these changes related to thiamine metabolism. Thus, our study aimed to analyze the effects of benfotiamine supplementation on brain thiamine absorption, as well as on parameters related to neuronal energy metabolism and disease progression in an experimental model of sporadic AD induced by intracerebroventricular injection of streptozotocin (STZ) in rats. The supplementation with 150 mg/kg of benfotiamine for 30 days increased the concentrations of thiamine diphosphate in the hippocampus and entorhinal cortex. This led to an improvement in mitochondria enzymes and insulin signaling pathway, with inactivation of GSK3α/β and ERK1/2, which are two tau-kinases related to the progression of AD, which could decrease tau hyperphosphorylation and apoptosis signaling. Besides, we observed an increased amount of Glun2b subunit of NMDA receptors, decreased inflammation, and improvement of cognitive deficit. Together, these results suggest that benfotiamine could be a potential therapeutic approach in the treatment of sporadic AD.

Low-Dose Ionizing Radiation Modulates Microglia Phenotypes in the Models of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aβ deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aβ pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aβ deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aβ accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aβ-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aβ deposition and memory loss.

Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice.

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6months to 10months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer's disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits. Graphical Abstract .

Huoluo Yinao decoction mitigates cognitive impairments after chronic cerebral hypoperfusion in rats

Ethnopharmacological relevanceHuoluo Yinao decoction (HLYND) has been used to ameliorate cognitive impairment induced by chronic cerebral hypoperfusion in clinical for years. However, the exact mechanisms remain unknown. Aim of the studyTo investigate the effects and mechanisms underlying HLYND-mediated improvement in cognitive deficits associated with chronic cerebral hypoperfusion. Materials and methodsThirty-six Sprague-Dawley rats were randomly allocated to three groups: sham, model, and HLYND. Daily administration of HLYND or volume-matched vehicle by gavage was initiated 1 day after bilateral carotid artery stenosis (BCAS) and continued for 42 days. The Morris water maze (MWM) test was used to assess cognitive functions from days 36–42. Via western blot and immunofluorescent staining, restoration of neuronal plasticity and remyelination of white matter were evaluated by analyzing the expression profiles of MAP-2, synaptophysin and MBP. In addition, macrophage/microglial activation was assessed by quantifying changes in Iba1, and macrophage/microglial polarization was assessed by changes in iNOS and CD16 (M1 markers), as well as Arg1 and CD206 (M2 markers). ResultsIn the MWM test, BCAS rats showed significantly extended escape latency and reduced platform crossing times, while those in the HLYND group had shortened escape latency and increased frequency of platform crossing. In addition, rats in the model group showed decreased levels and abnormal morphological changes of MAP-2, synaptophysin and MBP, whereas HLYND administration reversed these effects. As expected, Iba1 levels were elevated in both the model and HLYND groups but rats in the model group showed increased levels of the M1 markers, iNOS and CD16, and a correspondent decrease in the M2 marker, Arg1. In contrast, in the HLYND group, iNOS and CD16 levels were suppressed, while Arg1 levels were elevated. ConclusionsOur findings demonstrate that HLYND mitigates cognitive impairment after chronic cerebral hypoperfusion in rats through mechanisms involving increased neuronal plasticity and white matter remyelination, with a subtile modulation of macrophage/microglial polarization toward the M2 phenotype.