Abstract
Background
Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, ...dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD.
Methods
In this study, we constructed AD model mice by injecting Aβ
1–42
into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group.
Results
Aβ
1–42
i.c.v induced cognitive impairment and neuron damage in the brain of mice. At the same time, Aβ
1–42
i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aβ
1–42
treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aβ
1–42
treatment group.
Conclusions
The present findings suggested that Aβ in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.
Background
Immune system dysfunction has been proven to be an important pathological event in Alzheimer’s disease (AD). Mild cognitive impairment (MCI), as a transitional stage between normal ...cognitive function and AD, was an important research object for the screening of early diagnostic markers and therapeutic targets for AD. However, systematic assessment of peripheral immune system changes in MCI patients and consistent analysis with that in the CNS were still lacking.
Methods
Peripheral blood transcriptome data from the AddNeuroMed Cohort (
n
= 711) was used as a training dataset to assess the abundance of 24 immune cells through ImmuCellAI and to identify MCI-related immune signaling pathways and hub genes. The expression level of the immune hub gene was validated in peripheral blood (
n
= 587) and brain tissue (78 entorhinal cortex, 140 hippocampi, 91 temporal cortex, and 232 frontal cortex) validation datasets. Finally, reliable immune hub genes were applied for Gene Set Enrichment Analysis and correlation analysis of AD pathological characteristics.
Results
MCI patients have early changes in the abundance of various types of immune cells in peripheral blood, accompanied by significant changes in NF-kB, TNF, JAK-STAT, and MAPK signaling pathways. Five hub immune-related differentially expressed genes (NFKBIA, CD4, RELA, CASP3, and HSP90AA1) were screened by the cytoHubba plugin in Cytoscape and the least absolute shrinkage and selection operator (LASSO) regression. Their expression levels were significantly correlated with infiltration score and the abundance of monocytes, natural killer cells, Th2 T cells, T follicular helper cells, and cytotoxic T cells. After validation with independent datasets derived from peripheral blood and brain, RELA and HSP90AA1 were identified as two reliable immune hub genes in MCI patients and had consistent changes in AD. The Gene Set Enrichment Analysis (GSEA) showed that their expression levels were closely associated with Alzheimer’s disease, JAK-STAT, calcium signaling pathway, etc. In addition, the expression level of RELA was positively correlated with β- and γ-secretase activity and Braak stage. The expression level of HSP90AA1 was negatively correlated with α- and β-secretase activity.
Conclusion
Immune system dysfunction was an early event in AD. It provides a new target for the early diagnosis and treatment of AD.
Abstract Objectives To cross-sectionally explore the potential risk factors for rapid eye movement (REM) sleep behavior disorder (RBD) in a community cohort in Shanghai. Methods Based on the ...validated RBD screening questionnaire (RBDSQ), we identified individuals with probable RBD (pRBD) in 3635 community-dwelling residents (≥50 years old) from an urban community of Shanghai. Potential risk factors of pRBD, including age, sex, smoking, socioeconomic status, obesity, consumption of tea (surrogate for caffeine intake) and alcohol, medications and chronic disease status, were assessed via questionnaire. We used logistic regression to investigate the associations between these studied factors and pRBD after adjusting for age, sex and other studied factors. Results Based on the RBDSQ score ≥5, 2.70% (3.28% in men and 2.41% in women) participants were considered as pRBD. We found that lower education, presence of head injury, atrial fibrillation, hyperlipidemia, constipation, olfactory disturbance, and imbalance, use of alcoholic beverage, selective serotonin reuptake inhibitor, and benzodiazepine were associated with higher likelihood of having pRBD (P < 0.05 for all). In contrast, male sex, use of coffee or tea, smoking and other factors were not significantly association with altered risk of having pRBD. We did not find significant interaction between sex, age and these factors, in relation to pRBD risk. Conclusions In this community-based study of older adults, we identified several potential risk factors for concurrent pRBD, including environmental factors and vascular risk factors.
Cognitive decline poses a great concern to elderly people and their families. In addition to pharmacological therapies, several varieties of nonpharmacological intervention have been developed. Most ...training trials proved that a well-organized task is clinically effective in cognition improvement.
We will first review clinical trials of cognitive training for healthy elders, MCI and AD patients, respectively. Besides, potential neuroprotective and compensatory mechanisms in animal models of AD are discussed. Despite controversy, cognitive training has promising effect on cognitive ability. In animal model of AD, environmental enrichment showed beneficial effect for cognitive ability, as well as neuronal plasticity. Neurotrophin, neurotransmitter and neuromodulator signaling pathway were also involved in the process. Well-designed cognitive activity could benefit cognitive function, and thus life quality of patients and their families.
The positive effects of cognitive activity is closely related with neural plasticity, neurotrophin, neurotransmitter and neuromodulator signaling pathway changes.
...warm-up phenomena and grips myotonia were demonstrated. ...the limb muscle tone increased obviously. ...she possessed strabismus of the right eye Figure 1e, slurred speech and weak voice, claw ...finger deformity, and strephenopodia. ...p.P1158A in SCN4A wasfirst explored in our patients with MC.
Computerized multi-model training has been widely studied for its effect on delaying cognitive decline. In this study, we designed the first Chinese-version computer-based multi-model cognitive ...training for mild cognitive impairment (MCI) patients. Neuropsychological effects and neural activity changes assessed by functional MRI were both evaluated.
MCI patients in the training group were asked to take training 3-4 times per week for 6 months. Neuropsychological and resting-state fMRI assessment were performed at baseline and at 6 months. Patients in both groups were continuously followed up for another 12 months and assessed by neuropsychological tests again.
78 patients in the training group and 63 patients in the control group accomplished 6-month follow-up. Training group improved 0.23 standard deviation (SD) of mini-mental state examination, while control group had 0.5 SD decline. Addenbrooke's cognitive examination-revised scores in attention (p = 0.002) and memory (p = 0.006), as well as stroop color-word test interference index (p = 0.038) and complex figure test-copy score (p = 0.035) were also in favor of the training effect. Difference between the changes of two groups after training was not statistically significant. The fMRI showed increased regional activity at bilateral temporal poles, insular cortices and hippocampus. However, difference between the changes of two groups after another 12 months was not statistically significant.
Multi-model cognitive training help MCI patients to gained cognition benefit, especially in memory, attention and executive function. Functional neuroimaging provided consistent neural activation evidence. Nevertheless, after one-year follow up after last training, training effects were not significant. The study provided new evidence of beneficial effect of multi-model cognitive training.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. NAFLD is prevalent in about 30% of people worldwide. The lack of physical activity is ...considered as one of the risks for NAFLD, and approximately one-third of NAFLD patients hardly engage in physical activity. It is acknowledged that exercise is one of the optimal non-pharmacological methods for preventing and treating NAFLD. Different forms of exercise such as aerobic exercise, resistance exercise and even simply physical activity in a higher level can be beneficial in reducing liver lipid accumulation and disease progression for NAFLD patients. In NAFLD patients, exercise is helpful in lowering steatosis and enhancing liver function. The mechanisms underlying the prevention and treatment of NAFLD by exercise are various and complex. Current studies on the mechanisms have focused on the pro-lipolytic, anti-inflammatory, and antioxidant and lipophagy. Promotion of lipophagy is regarded as an important mechanism for prevention and improvement of NAFLD by exercise. Recent studies have investigated the above mechanism, yet the potential mechanism has not been completely elucidated. Thus, in this review, we cover the recent advances of exercise-promoted lipophagy in NAFLD treatment and prevention. Furthermore, given the fact that exercise activates SIRT1, we discuss the possible regulatory mechanisms of lipophagy by SIRT1 during exercise. These mechanisms need to be verified by further experimental studies.
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•There is a close interaction between gut microbiota, immune system and Alzheimer's disease (AD).•The inherent structure and the metabolites of gut microbiota play a key k role in the regulation of ...AD through numerous inflammatory pathways.•Several intervention strategies through modifying the of gut microbiota are important potential treatments for AD.
In the past decade, numerous studies have demonstrated the close relationship between gut microbiota and the occurrence and development of Alzheimer’s disease (AD). However, the specific mechanism is still unclear. Both the neuroinflammation and systemic inflammation serve as the key hubs to accelerate the process of AD by promoting pathology and damaging neuron. What's more, the gut microbiota is also crucial for the regulation of inflammation. Therefore, this review focused on the role of gut microbiota in AD through inflammatory pathways. Firstly, this review summarized the relationship and interaction among gut microbiota, inflammation, and AD. Secondly, the direct and indirect regulatory effects of gut microbiota on AD through inflammatory pathways were described. These effects were mainly mediated by the component of the gut microbiota (lipopolysaccharides (LPS) and amyloid peptides), the metabolites of bacteria (short-chain fatty acids, branched amino acids, and neurotransmitters) and functional by-products (bile acids). In addition, potential treatments (fecal microbiota transplantation, antibiotics, probiotics, prebiotics, and dietary interventions) for AD were also discussed through these mechanisms. Finally, according to the current research status, the key problems to be solved in the future studies were proposed.
CSF1R
-related leukoencephalopathy is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (
CSF1R
) gene mutation. Few ...studies have investigated the intrinsic brain alternations of patients with
CSF1R
-related leukoencephalopathy. We aim to evaluate the structural and functional changes in those patients. Seven patients with
CSF1R
-related leukoencephalopathy and 15 age-matched healthy controls (HCs) underwent multimodal magnetic resonance imaging (MRI), including high-resolution T1-weighted imaging, T2-weighted fluid attenuated inversion recovery imaging, diffusion-weighted imaging, diffusion kurtosis imaging (DKI) and resting-state functional MRI. First, to detect structural alterations, the gray matter volumes were compared using voxel-based morphometry analyses. Second, DKI parametric maps were used to evaluate the white matter (WM) connectivity changes. Finally, we constructed a seed-based resting-state functional connectivity matrix based on 90 regions of interest and examined the functional network changes of
CSF1R
-related leukoencephalopathy. Unlike the HCs, patients with
CSF1R
-related leukoencephalopathy predominantly had morphological atrophy in the bilateral thalamus and left hippocampus. In addition, the abnormal diffusivity was mainly distributed in the splenium of the corpus callosum, periventricular regions, centrum semiovale, subcortical U-fibers and midline cortex structures. Moreover, the patients had significantly reduced functional connectivity between the bilateral caudate nucleus and their contralateral hippocampus. Therefore, in addition to hyperintensity on the T2-weighted images,
CSF1R
-related leukoencephalopathy also showed abnormal structural and functional alterations, including subcortical atrophy and reduced functional connectivity, as well as altered diffuse parameters in the WM and subcortical regions. These findings expand our understanding of the potential pathophysiologic mechanism behind this hereditary disease.