Chronic stress induces insulin resistance and enhances cognitive impairment in AD.

BACKGROUND: Chronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. METHODS: Male 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). RESULTS: Four weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aß42 and Aß40 in wild-type mice. CONCLUSIONS: Chronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

The Efficacy of Morodan in Combination with Rabeprazole for the Treatment of Chronic Gastritis and its Impact on Gastric Mucosal Repair.

Objective: This study aimed to investigate the application and effectiveness of Morodan combined with rabeprazole in patients with chronic gastritis, focusing on its impact on gastric mucosa repair. Methods: A cohort of 109 patients diagnosed with chronic gastritis, who received treatment at our hospital between January 2020 and January 2021, were included in this study. Among them, 56 patients were assigned to the control group and received treatment with rabeprazole alone, while 53 were assigned to the research group and received a combination therapy of Morodan and rabeprazole. A comparative analysis was conducted between the two groups, assessing clinical efficacy, gastric mucosa repair effects, serum-related factors, and the incidence of adverse reactions. Results: The research group exhibited a higher total effective rate of treatment (94.64%) compared to the control group (79.25%) (P < .05). Following treatment, the research group showed lower levels of pepsinogen II, serum transforming growth factor α, serum epidermal growth factor, tumor necrosis factor-α, interleukin 6, and C-reactive protein compared to the control group (P < .05). Additionally, the research group displayed higher levels of pepsinogen I compared to the control group (P < .05). There was no significant difference in the incidence of adverse reactions between the research group and the control group (P > .05). Conclusions: The combination therapy of Morodan and rabeprazole demonstrates efficacy in the treatment of chronic gastritis. It promotes gastric mucosa repair, reduces inflammatory damage, and exhibits a higher safety profile with no significant increase in adverse reactions. This treatment approach holds a higher clinical application value.

Microstate feature fusion for distinguishing AD from MCI.

Electroencephalogram (EEG) microstates provide powerful tools for identifying EEG features due to their rich temporal information. In this study, we tested whether microstates can measure the severity of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in patients and effectively distinguish AD from MCI. We defined two features using transition probabilities (TPs), and one was used to evaluate between-group differences in microstate parameters to assess the within-group consistency of TPs and MMSE scores. Another feature was used to distinguish AD from MCI in machine learning models. Tests showed that there were between-group differences in the temporal characteristics of microstates, and some kinds of TPs were significantly correlated with MMSE scores within groups. Based on our newly defined time-factor transition probabilities (TTPs) feature and partial accumulation strategy, we obtained promising scores for accuracy, sensitivity, and specificity of 0.938, 0.923, and 0.947, respectively. These results provide evidence for microstates as a neurobiological marker of AD.

Heterogenous Subtypes of Late-Life Depression and Their Cognitive Patterns: A Latent Class Analysis.

Background: Late-life depression (LLD), characterized by cognitive deficits, is considered heterogeneous across individuals. Previous studies have identified subtypes with diverse symptom profiles, but their cognitive patterns are unknown. This study aimed to investigate the subtypes of LLD and the cognitive profile of each group. Methods: In total, 109 depressed older adults were enrolled. We performed latent class analysis using Geriatric Depression Scale items as indicators to generate latent classes. We compared the sociodemographic and clinical characteristics with cognitive functions between groups and conducted regression analysis to investigate the association between class membership and variables with significant differences. Results: Two classes were identified: the "pessimistic" group was characterized by pessimistic thoughts and the "worried" group with a relatively high prevalence of worry symptoms. The two groups did not differ in sociodemographic characteristics. The "pessimistic" group showed a higher rate of past history of depression and lower age of onset. The "worried" group had more physical comorbidities and a higher rate of past history of anxiety. The "pessimistic" group was more impaired in general cognitive function, executive function, information processing speed, and attention. Lower general and executive functions were associated with the membership in the "pessimistic" group. Conclusions: Subjects with pessimistic symptoms and subjects with a propensity to worry may form two distinct subtypes of late-life depression with different cognitive profiles. Further, the cognitive evaluation of subjects with pessimistic symptoms is of utmost importance.

Case Report: Insulinoma Presenting as Excessive Daytime Somnolence.

Currently, undiagnosed insulinomas remain a difficult clinical dilemma because its symptoms in most cases can easily be misdiagnosed as other diseases. In this article, we present the case of a 14-year-old girl who presented to our hospital with recurrent episodes of excessive daytime sleepiness and abnormal behavior during sleep that had been going on for 3 months. Insulinoma is a rare neuroendocrine tumor that causes excessive release of insulin, resulting in episodes of hypoglycemia. It usually manifests as autonomic sympathetic symptoms. These symptoms resolved rapidly with the administration of glucose. After successful removal of the tumor, daytime sleepiness and abnormal nighttime behavior of the patient did not reappear.

Risk factors associated with postoperative intensive care unit delirium in patients undergoing invasive mechanical ventilation following acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: This study was performed to determine the risk factors associated with intensive care unit delirium (ICUD) in patients undergoing invasive mechanical ventilation (IMV) secondary to acute exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Data involving 620 patients undergoing IMV secondary to acute exacerbation of COPD from 2009 to 2019 at the First Hospital of Hebei Medical University were retrospectively analysed. The primary endpoint was the risk factors associated with developing ICUD. Univariable and multivariable logistic regression analyses were used to identify these risk factors. RESULTS: Of 620 patients, 93 (15.0%) developed ICUD. In the multivariable analysis, risk factors that were significantly associated with ICUD were increased age, male sex, alcoholism with active abstinence, current smoking, stage 3 acute kidney injury (AKI), and an American Society of Anesthesiologists (ASA) physical status of III. CONCLUSION: This study showed that increasing age, male sex, alcoholism with active abstinence, current smoking, stage 3 AKI, and an ASA physical status of III might be associated with a risk of developing ICUD. Even if these risk factors are unaltered, they provide a target population for quality improvement initiatives.

hUC-MSCs ameliorated CUMS-induced depression by modulating complement C3 signaling-mediated microglial polarization during astrocyte-microglia crosstalk.

BACKGROUND: Major depressive disorder (MDD) has been shown to be related to immune inflammation and the complement system. Previous studies have suggested that human umbilical cord mesenchymal stem cells (hUC-MSCs) play an important role in inflammatory diseases. METHODS: hUC-MSCs were administered into chronic unpredictable mild stress model (CUMS) mice through the tail vein once a week for 4 weeks. After the administration of hUC-MSCs, the depression-like and anxiety-like phenotypes, neuronal histopathology, synaptic-related protein expression and inflammatory index of the mice were assessed. Microglial M1/M2 polarization and the expression of C3a in astrocytes and C3aR in microglia was detected by immunofluorescence co-localization. Then, CUMS mice were injected with a C3aR antagonist, and the expression of C3a and C3aR and microglial polarization were observed. RESULTS: Based on the sucrose preference and tail suspension tests, hUC-MSCs ameliorated the depression-like behaviors of CUMS mice. Additionally, the anxiety-like behaviors of CUMS mice in the open-field and plus-maze tests were improved after the administration of hUC-MSCs. hUC-MSCs altered microglia polarization by alleviating complement C3a-C3aR signaling activation, which decreased pro-inflammatory factor levels and increased anti-inflammatory factor levels, alleviating neuronal damage and synaptic deficits. CONCLUSION: hUC-MSCs have therapeutic effects on anxiety-like and depressive-like phenotypes caused by CUMS. They can alter the polarization of microglia by inhibiting C3a-C3aR signaling to reduce neuroinflammation.

High Frequency Repetitive Transcranial Magnetic Stimulation Alleviates Cognitive Impairment and Modulates Hippocampal Synaptic Structural Plasticity in Aged Mice.

Normal aging is accompanied by hippocampus-dependent cognitive impairment, which is a risk factor of Alzheimer's disease. This study aims to investigate the effect of high frequency-repetitive transcranial magnetic stimulation (HF-rTMS) on hippocampus-dependent learning and memory in aged mice and explore its underlying mechanisms. Forty-five male Kunming mice (15 months old) were randomly divided into three groups: aged sham, 5 Hz rTMS, and 25 Hz rTMS. Two sessions of 5 Hz or 25 Hz rTMS comprising 1,000 pulses in 10 trains were delivered once a day for 14 consecutive days. The aged sham group was treated by the reverse side of the coil. In the adult sham group, 15 male Kunming mice (3 months old) were treated the same way as the aged sham group. A Morris water maze (MWM) was conducted following the stimulation, and synaptic ultrastructure was observed through a transmission electron microscope. HF-rTMS improved spatial learning and memory impairment in the aged mice, and 5 Hz was more significant than 25 Hz. Synaptic plasticity-associated gene profiles were modified by HF-rTMS, especially neurotrophin signaling pathways and cyclic adenosine monophosphate response element binding protein (CREB) cofactors. Compared to the aged sham group, synaptic plasticity-associated proteins, i.e., synaptophysin (SYN) and postsynaptic density (PSD)-95 were increased; brain-derived neurotrophic factor (BDNF) and phosphorylated CREB (pCREB) significantly increased after the 5 Hz HF-rTMS treatment. Collectively, our results suggest that HF-rTMS ameliorated cognitive deficits in naturally aged mice. The 5 Hz rTMS treatment significantly enhanced synaptic structural plasticity and activated the BDNF/CREB pathway in the hippocampus.

Comparison of Quantitative Electroencephalogram During Sleep in Depressed and Non-Depressed Patients with Parkinson's Disease.

BACKGROUND Depression is one of the most important factors affecting quality of life in Parkinson's patients. Most research on Parkinson's disease with depression has focused on neuroimaging, and there have been few quantitative electroencephalogram studies. Sleep is a biomarker for depression; therefore, the aim of this study was to identify differences in quantitative electroencephalograms during sleep in depressed and non-depressed patients with Parkinson's disease. MATERIAL AND METHODS We assessed 38 Parkinson's disease patients (26 depressed patients, 12 non-depressed patients) and 20 normal subjects using the Geriatric Depressive Scale for Depressive Symptoms and quantitative electroencephalogram analysis of amplitude of different frequency bands in different sleep stages using Met-lab software and Fast Fourier Transformation. RESULTS Non-rapid eye moment 2 and the Frontal 4 Electrode amplitude in the delta and theta ranges were progressively and significantly greater in the depressed-Parkinson's disease group (p<0.05) than in the control group. In the depressed Parkinson's disease group, from the comparison of non-rapid eye moment 2 and rapid eye moment, in Frontal 4 the amplitude in the delta ranges of non-rapid eye moment 2 was greater than in the non-depressed group, and in Central 3, Central 4, Occipital 1, and Occipital 2, the amplitudes in the beta ranges of rapid eye moment were greater (p<0.05) than in the non-depressed group. CONCLUSIONS The higher amplitude in theta in frontal areas in NREM2 and the higher amplitude in beta in parietal and occipital lobe areas in REM relative to NREM2 were significantly different in depressed and non-depressed patients with Parkinson's disease.

Long-Term DL-3-n-Butylphthalide Treatment Alleviates Cognitive Impairment Correlate With Improving Synaptic Plasticity in SAMP8 Mice.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide. AD is characterized by mild cognitive impairment at onset, irreversibly progressing with age to severe neurodegeneration and cognitive deficits in the late stages. Unfortunately, no effective treatments exist to prevent or delay the cognitive symptoms of AD. Studies have shown that DL-3-n-butylphthalide (DL-NBP) alleviates cognitive impairment induced by amyloid-ß in mice by reducing oxidative stress, inhibiting apoptosis, and decreasing tau phosphorylation. In this study, we examined the effects of DL-NBP administration on cognitive function in the senescence-accelerated mouse prone 8 (SAMP8) model of age-related dementia. DL-NBP treatment for 3 months alleviated cognitive impairment in SAMP8 mice as assessed by performance in the Morris water maze test. Moreover, DL-NBP significantly increased the expression of synaptophysin and postsynaptic density protein 95 in the hippocampus of SAMP8 mice, indicative of a protective effect on hippocampal structural synaptic plasticity. In addition, brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling, previously shown to promote synaptic plasticity, was significantly enhanced by the DL-NBP administration. Our findings suggest that DL-NBP is a potential drug candidate for the treatment of cognitive impairment in AD and may serve as the foundation for further research into the development of AD drugs.

Role of mammalian target of rapamycin signaling in autophagy and the neurodegenerative process using a senescence accelerated mouse-prone 8 model.

The mammalian target of rapamycin (mTOR) kinase is an inhibitor of autophagy, which is an intracellular system involved in the degradation of long-lived proteins and organelles in lysosomes. Recent evidence suggests that the steady incline in mTOR function during aging may be associated with the cognitive decline related to aging and may also promote development of Tau pathology. At present, the senescence accelerated mouse prone 8 (SAMP8) is an experimental model that has been proposed for the study of age-related neurodegenerative changes associated with aging. In the present study, mTOR signaling in the hippocampus of SAMP8 newborn mice and in the control-strain SAMR1 mice was investigated. Consequently, hyper phosphorylated Tau (pS199 or pS396) and upregulated mTOR activity were observed in SAMP8 when compared with SAMR1; however, 0.5 µM rapamycin administration significantly reduced the levels of phosphorylated Tau and p70S6K (pT389) in SAMP8 mice. Related to these findings, SAMP8 exhibited an increase in the neuronal loss of hippocampus that was associated with lower levels of anti-apoptotic proteins. These results indicate that mTOR signaling participates in the neurodegenerative process and rapamycin administration may protect neurons of SAMP8 mice and may have a potential role in curing cognitive decline.

Effects of Chronic Stress on Cognition in Male SAMP8 Mice.

BACKGROUND/AIMS: Chronic stress can lead to cognitive impairment. Senescence-accelerated mouse prone 8 (SAMP8) is a naturally occurring animal model that is useful for investigating the neurological mechanisms of Alzheimer's disease. Here we investigated the impact and mechanisms of chronic stress on cognition in male SAMP8 mice. METHODS: Male 6-month- old SAMP8 and SAMR1 (senescence-accelerated mouse resistant 1) mice strains were randomly divided into 4 groups. Mice in the unpredictable chronic mild stress (UCMS) groups were exposed to diverse stressors for 4 weeks. Then, these mice performed Morris water maze (MWM) test to assess the effect of UCMS on learning and memory. To explore the neurological mechanisms of UCMS on cognition in mice, we evaluated changes in the expression of postsynaptic density 95 (PSD95) and synaptophysin (SYN), which are essential proteins for synaptic plasticity. Five mice from each group were randomly chosen for reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis of SYN and PSD95. RESULTS: The Morris water maze experiment revealed that the cognitive ability of the SAMP8 mice decreased with brain aging, and that chronic stress aggravated this cognitive deficit. In addition, chronic stress decreased the mRNA and protein expression of SYN and PSD95 in the hippocampus of the SAMP8 mice; however, the SAMR1 mice were unaffected. CONCLUSION: Our results demonstrate that decreased cognition and synaptic plasticity are related to aging. Moreover, we show that chronic stress aggravated this cognitive deficit and decreased SYN and PSD95 expression in the SAMP8 mice. Furthermore, the SAMP8 mice were more vulnerable to the detrimental effects of chronic stress on cognition than the SAMR1 mice. Our results suggest that the neurological mechanisms of chronic stress on cognition might be associated with a decrease in hippocampal SYN and PSD95 expression, which is critical for structural synaptic plasticity.

Age-related autophagy alterations in the brain of senescence accelerated mouse prone 8 (SAMP8) mice.

Autophagy is responsible for the degradation of long-lived proteins and damaged organelles intracellular, even extracellular,and autophagy is proved to have relationship with Alzheimer's disease (AD) and aging. The senescence accelerated mouse prone 8 (SAMP8) was a non-genetically modified mice widely used as a rodent model of aging and senile dementia. However, little was known about the age-related changes of autophagy in the brain of SAMP8 mice. To better understand the precise relationship between aging, autophagy and neurodegeneration, we explored the time course of cognitive ability, ubiquitin-positive inclusions, ultrastructure of neurons and detected the expression of LC3 and Beclin 1 protein in different brain regions of 2, 7 and 12-month-old SAMP8 and SAMR1 mice. We found that 7 and 12-month-old SAMP8 mice presented cognitive decline and ubiquitinated proteins enhanced. In the hippocampal neurons of 12-month-old SAMP8 mice, lots of dense clumps and autophagic vacuoles were found in the cytoplasm and axons. The LC3-II expression showed an increase in hippocampus and cortex of 7 and 12-month-old SAMP8 mice. The expression of Beclin 1 displayed a significant increase in 7 months old and a decline in 12 months old mice. Based on these data, we suggest that the autophagic activity maybe increase reactively at the beginning of AD and then showed a decline with aging, and the pathological changes of 12-month-old SAMP8 mice are more similar to the late-onset AD in the perspective of autophagy.

Microglial activation and age-related dopaminergic neurodegeneration in MPTP-treated SAMP8 mice.

Senescence-accelerated mouse prone 8 (SAMP8) has an early onset of senility and a shorter life span, providing with cognitive impairment. Contrasted with C57BL/6 mouse, which is most commonly used in the study of Parkinson's disease (PD), SAMP8 needs shorter period of breeding and might be good candidate for the investigation of cognitive impairment in PD. Studies had shown the increase of sensibility to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) with aging in C57BL/6 mouse. However, the sensitivity of MPTP neurotoxicity depends on the strains of animal and the exact mechanisms of the progression of PD promoted by aging is lack of consensus. Here, we showed after MPTP injection, the spontaneous activity of both young (3-month-old) and old (6-month-old) SAMP8 decreased dramatically, and the old mice required longer recovery time. Immunohistochemical and immunoblot analysis revealed that old mice displayed significant reductions in the dopaminergic neuron numbers and tyrosine hydroxylase (TH) protein. Microglia protein (CD11b) in the striatum of old mice increased more pronouncedly than that in the young mice from 24 h to 3 days. Inducible nitric oxide synthase (iNOS) in the striatum remarkably increased, however, no discernible difference between the two groups was found. These results suggested that the sensibility to MPTP increased with aging in SAMP8. A greater increase of microglial activation in old mice may be a possible mechanism to explain how advancing age predisposes the dopamine system to parkinsonism. The MPTP-SAMP8 model will start a new consideration for the study of PD.

[Neurotoxicity effect of MPP+ on primary cultured mesencephalon neurons of SAMP8 mouse].

AIM: To investigate the effect of MPP+ on the midbrain neurons of SAMP8 mouse in vitro, which provide the cell model for PD study. METHODS: SAMP8 mouse primary midbrain cell cultures were obtained from mice within 1 day after birth. On the sixth day after culturing, the cultures were treated with 100 micromol/L of MPP+ for 6 hours, 9 hours, 12 hours and 24 hours, then the cells were fixed and followed by immunofluorescence or Western blot analysis for the expressed location and the level of TH respectively. RESULTS: MPP+ led to the morphological changes of primary cultured midbrain neurons of SAMP8 mouse. The neurons had intact morphous with strong immunoreactivity, many and long dendrites in control group. Compared with the control group, the neurons had fewer and thinness dendrites with weak immunoreactivity in MPP+ group. MPP+ significantly decreased midbrain neurons numbers with marked decrease of TH protein levels after its treatment for 9 h. CONCLUSION: MPP+ had neurotoxicity effect on primary cultured midbrain neurons of SAMP8 mouse. Since MPP+ led to marked decrease of neuronal numbers and TH protein levels, it is suggested that MPP+ can cause the DA neuronal degeneration in primary midbrain cell cultures.