Current Alzheimer research最新文献

Objectives: Cerebral blood flow (CBF) is an important index for measuring brain function. Studies have shown that regional CBF changes inconsistently in mild cognitive impairment (MCI). Arterial spin labeling (ASL) is widely used in the study of CBF in patients with MCI. However, alterations in CBF connectivity in these patients remain poorly understood.

Methods: In this study, 3D pseudo-continuous arterial spin labeling (3D-pCASL) technology was used to investigate the changes in regional CBF and CBF connectivity between 32 MCI patients and 32 healthy controls. The normalized CBF was used to reduce inter-subject variations. Both group comparisons in the CBF and correlations between CBF alterations and cognitive scores were assessed. CBF connectivity of brain regions with regional CBF differences was also compared between groups.

Results: We found that compared with that in controls, the CBF was significantly reduced in the left superior parietal gyrus in MCI patients, whereas it was increased in the left precentral gyrus, right superior temporal gyrus, right putamen, and left supplementary motor area. In patients with MCI, significant correlations were identified between CBF and neuropsychological scales. Importantly, MCI patients exhibited CBF disconnections between the left supplementary motor area and the left superior parietal gyrus.

Conclusion: This study found that there are not only changes in regional CBF but also in CBF connectivity patterns in MCI patients compared with controls. These observations may provide a novel explanation for the neural mechanism underlying the pathophysiology in patients with Alzheimer's disease and MCI.

The issue of the genetics in brain imaging phenotypes serves as a crucial link between two distinct scientific fields: neuroimaging genetics (NG). The articles included here provide solid proof that this NG link has considerable synergy. There is a suitable collection of articles that offer a wide range of viewpoints on how genetic variations affect brain structure and function. They serve as illustrations of several study approaches used in contemporary genetics and neuroscience. Genome-wide association studies and candidate-gene association are two examples of genetic techniques. Cortical gray matter structural/volumetric measures from magnetic resonance imaging (MRI) are sources of information on brain phenotypes. Together, they show how various scientific disciplines have benefited from significant technological advances, such as the single-nucleotide polymorphism array in genetics and the development of increasingly higher-resolution MRI imaging. Moreover, we discuss NG's contribution to expanding our knowledge about the heterogeneity within Alzheimer's disease as well as the benefits of different network analyses.

Background: Alzheimer's disease (AD) is a persistent neuropathological injury that manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation, and apoptosis. Synapsin 1 (SYN1), a neuronal phosphoprotein, is believed to be responsible for the pathology of AD.

Objective: This study aimed to elucidate the exact role of SYN1 in ameliorating AD and its potential regulatory mechanisms.

Methods: The AD dataset GSE48350 was downloaded from the GEO database, and SYN1 was focused on differential expression analysis and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. After establishing an AD rat model, they were treated with RNAi lentivirus to trigger SYN1 overexpression. The amelioration of SYN1 in AD-associated behavior was validated using multiple experiments (water maze test and object recognition test). SYN1's repairing effect on the important factors in AD was confirmed by detecting the concentration of inflammatory factors (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α), neurotransmitters (acetylcholine (ACh), dopamine (DA), and 5-hydroxytryptophan (5-HT)) and markers of oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS)). Molecular biology experiments (qRT-PCR and western blot) were performed to examine AD-related signaling pathways after SYN1 overexpression.

Results: Differential expression analysis yielded a total of 545 differentially expressed genes, of which four were upregulated and 541 were downregulated. The enriched pathways were basically focused on synaptic functions, and the analysis of the protein- protein interaction network focused on the key genes in SYN1. SYN1 significantly improved the spatial learning and memory abilities of AD rats. This enhancement was reflected in the reduced escape latency of the rats in the water maze, the significantly extended dwell time in the third quadrant, and the increased number of crossings. Furthermore, the results of the object recognition test revealed reduced time for rats to explore familiar and new objects. After SYN1 overexpression, the cAMP signaling pathway was activated, the phosphorylation levels of the CREB and PKA proteins were elevated, and the secretion of neurotransmitters such as ACh, DA, and 5-HT was promoted. Furthermore, oxidative stress was suppressed, as supported by decreased levels of MDA and ROS. Regarding inflammatory factors, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in AD rats with SYN1 overexpression.

Conclusion: SYN1 overexpression improves cognitive function and promotes the release of various neurotransmitters in AD rats by inhibiting oxidative stress and inflammatory responses through cAMP signaling pathway activation. These findings may provide a theoretical basis for the targeted diagnosis and trea

Objectives: Alzheimer's disease (AD) and/or dementia is a prevalent neurocognitive disorder primarily affecting individuals over the age of 65. Identifying specific causes of AD and/or dementia can be challenging, with emerging evidence suggesting a potential association with autoimmune inflammatory conditions such as rheumatoid arthritis (RA). This study aimed to assess the prevalence rate of AD and/or dementia among Medicare beneficiaries reporting an autoimmune disorder. Additionally, this study sought to identify the comparative prevalence of AD and/or dementia in patients with an autoimmune disorder who were using disease-modifying antirheumatic drugs (DMARDs) compared to those not using DMARDs.

Methods: Cross-sectional secondary data analyses were conducted on Medicare Current Beneficiary Survey (MCBS) data from 2017 and 2018. The MCBS data consists of a nationally representative sample of the Medicare population, a population that is largely 65 and older, and provides de-identified patient information. Patients from this dataset with a self-reported autoimmune disorder were included in the analyses. Descriptive analyses were conducted on demographic variables, chronic conditions, and medication use. The prevalence of AD and/or dementia was compared between patients with and without an autoimmune disorder. A backward stepwise selection regression was used to identify the risk factors associated with the prevalence of AD and/or dementia.

Results: The study included 18,929 Medicare beneficiaries, with 4,405 identified as having one autoimmune disorder. The prevalence of AD and/or dementia was significantly higher in patients with an autoimmune disorder. The multivariate regression showed that RA was significantly associated with a higher risk of AD and/or dementia. Other demographic factors, including advanced age, African-American or Hispanic ethnicity, low body mass index, and chronic conditions of ischemic heart disease, history of myocardial infarction, history of stroke, depression, mental health disorder(s), and traumatic brain injury also showed statistically significant associations with AD and/or dementia. Patients using DMARDs demonstrated a reduced likelihood of having AD and/or dementia, compared to patients not using DMARDs.

Conclusion: This study provides evidence of an association between RA and increased risk of AD and/or dementia. The findings suggest that DMARD use may have a protective effect against the development of AD and/or dementia in patients with an autoimmune disorder.

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's Disease (AD). However, the detailed mechanism underlying T2DM-related AD remains unknown. In DM, many types of advanced glycation end-products (AGEs) are formed and accumulated. In our previous study, we demonstrated that Glyceraldehyde (GA)-derived Toxic Advanced Glycation End-products (Toxic AGEs, TAGE) strongly showed cytotoxicity against neurons and induced similar alterations to those observed in AD. Further, GA induced dysfunctional neurite outgrowth via TAGE-β-- tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation. Herein, we provide a perspective on the possibility that T2DM increases the probability of AD onset and accelerates its progression.

The Alzheimer's disease (AD) continuum is a unique spectrum of cognitive impairment that typically involves the stages of subjective memory complaints (SMC), mild cognitive impairment (MCI), and AD dementia. Neuropsychiatric symptoms (NPS), such as apathy, anxiety, stress, and depression, are highly common throughout the AD continuum. However, there is a dearth of research on how these NPS vary across the AD continuum, especially SMC. There is also disagreement on the effects of specific NPS on each stage of the AD continuum due to their collinearity with other NPS, cognitive decline, and environmental factors (e.g., stress). In this article, we conduct a novel perspective review of the scientific literature to understand the presence of NPS across the AD continuum. Specifically, we review the effects of apathy, depression, anxiety, and stress in AD, MCI, and SMC. We then build on this knowledge by proposing two theories of NPS' occurrence across the AD continuum. Consequently, we highlight the current landscape, limitations (e.g., differing operationalization), and contentions surrounding the NPS literature. We also outline theories that could clear up contention and inspire future NPS research.

Background: Alzheimer's disease is the most common neurodegenerative disorder. Recent development in sciences has also identified the pivotal role of microRNAs (miRNAs) in AD pathogenesis.

Objectives: We proposed a novel method to identify AD pathway-specific statistically significant miRNAs from the targets of known AD drugs. Moreover, microRNA scaffolds and corresponding drug scaffolds of different pathways were also discovered.

Material and methods: A Wilcoxon signed-rank test was performed to identify pathway-specific significant miRNAs. We generated feed-forward loop regulations of microRNA-TF-gene-based networks, studied the minimum free energy structures of pre-microRNA sequences, and clustered those microRNAs with their corresponding structural motifs of robust transcription factors. Conservation analyses of significant microRNAs were done, and the phylogenetic trees were constructed. We identified 3'UTR binding sites and chromosome locations of these significant microRNAs.

Results: In this study, hsa-miR-4261, hsa-miR-153-5p, hsa-miR-6766, and hsa-miR-4319 were identified as key miRNAs for the ACHE pathway and hsa-miR-326, hsa-miR-6133, hsa-miR-4251, hsa-miR-3148, hsa-miR-10527-5p, hsa-miR-527, and hsa-miR-518a were identified as regulatory miRNAs for the NMDA pathway. These miRNAs were regulated by several AD-specific TFs, namely RAD21, FOXA1, and ESR1. It has been observed that anisole and adamantane are important chemical scaffolds to regulate these significant miRNAs.

Conclusion: This is the first study that developed a detailed correlation between known AD drug scaffolds and their AD target-specific miRNA scaffolds. This study identified chromosomal locations of microRNAs and corresponding structural scaffolds of transcription factors that may be responsible for miRNA co-regulation for Alzheimer's disease. Our study provides hope for therapeutic improvements in the existing microRNAs by regulating pathways and targets.

Background: Along with the problem of population aging, the prevalence of dementia is gradually increasing. Associations between vitamin D deficiency (VDD) and cognitive functions remain unclear.

Objectives: We aimed to determine the relationship between VDD and changes in cognitive performance in community-dwelling older adults.

Methods: In this longitudinal cohort study, participants aged ≥65 years were enrolled in March, 2016. The serum level of 25-hydroxy-vitamin D was analyzed by liquid-chromatography-tandem-- mass-spectrometry at baseline. VDD was defined as less than 20 ng/mL. All participants completed a health status questionnaire. Cognitive functions were evaluated by the Wechsler Adult Intelligence Scale-Revised in China at baseline and each visit. The linear mixed-effects model was utilized to examine the association between baseline VDD and changes in cognitive functions.

Results: In total, 866 participants were included in our study, with a mean duration of 3 years. VDD was markedly associated with lower full intelligence quotient (FIQ) (β: -3.355, 95% confidence interval [CI]:-4.165,-2.545), verbal intelligence quotient (VIQ) (β: -3.420, 95%CI: -4.193,-2.647), performance intelligence quotient (PIQ) (β: -2.610, 95%CI: -3.683,-1.537), comprehension (β: -0.630, 95%CI: -1.022,-0.238), information (β: -0.354, 95%CI: -0.699,-0.008), arithmetic (β: -1.065, 95%CI: -1.228,-0.902), digit span (β: -0.370, 95%CI: -0.547,-0.192), vocabulary (β: -0.789, 95%CI: -1.084,-0.493), picture completion (β: -0.391, 95%CI: -0.761,-0.022), block design (β: -0.412, 95%CI: -0.697,-0.127), picture arrangement (β: -0.542, 95%CI: -0.909,-0.174), and object assembly (β: -0.492, 95%CI: -0.818,-0.165) than those with adequacy.

Conclusion: A higher frequency of VDD was associated with lower scores of FIQ, VIQ, PIQ and subtests on memory and executive function. Future randomized controlled trials are warranted to further verify the conclusions.

Aim: To evaluate the potential beneficial role of Capsaicin in cognitive dysfunction, mitochondrial impairment, and oxidative damage induced by scopolamine in mice.

Background: Capsaicin is the chief phenolic component present in red chili and is responsible for its pungent and spicy flavor. It affects TRPV1 channels in nociceptive sensory neurons and is present in the hippocampus, and hypothalamus of the brains of rodents and humans.

Objective: The main objective is to investigate the effective role of capsaicin in attenuating cognitive dysfunction, mitochondrial impairment, and oxidative damage induced by scopolamine in mice and examine the feasible mechanisms.

Methods: Various doses of capsaicin (5, 10, and 20 mg/kg) were given orally to mice daily for 7 consecutive days after the administration of scopolamine. Various behavioral tests (motor coordination, locomotor counts, hole board test) and biochemical assay (Pro-inflammatory cytokines, catalase, lipid peroxidation, nitrite, reduced glutathione, and superoxide dismutase), mitochondrial complex (I, II, III, and IV) enzyme activities, and mitochondrial permeability transition were evaluated in the distinct regions of the brain.

Results: Scopolamine-treated mice showed a considerable reduction in the entries and duration in the light zone as well as in open arms of the elevated plus maze. Interestingly, capsaicin at different doses reversed the anxiety, depressive-like behaviors, and learning and memory impairment effects of scopolamine. Scopolamine-administered mice demonstrated substantially increased pro-inflammatory cytokines levels, impaired mitochondrial enzyme complex activities, and increased oxidative damage compared to the normal control group. Capsaicin treatment reinstated the reduced lipid peroxidation, nitric oxide, catalase, superoxide dismutase, reduced glutathione activity, decreasing pro-inflammatory cytokines and restoring mitochondrial complex enzyme activities (I, II, III, and IV) as well as mitochondrial permeability. Moreover, the IL-1β level was restored at a dose of capsaicin (10 and 20 mg/kg) only. Capsaicin reduced the scopolamine-induced acetylcholinesterase activity, thereby raising the acetylcholine concentration in the hippocampal tissues of mice. Preservation of neuronal cell morphology was also confirmed by capsaicin in histological studies. From the above experimental results, capsaicin at a dose of 10 mg/kg, p.o. for seven consecutive days was found to be the most effective dose.

Conclusion: The experiential neuroprotective effect of capsaicin through the restoration of mitochondrial functions, antioxidant effects, and modulation of pro-inflammatory cytokines makes it a promising candidate for further drug development through clinical setup.

Background: To evaluate the efficacy and pharmacological mechanisms of resveratrol in Alzheimer's disease (AD) patients.

Methods: We conducted a thorough exploration of existing randomized controlled trials concerning the treatment of Alzheimer's disease patients using resveratrol, utilizing accessible open databases. Quantitative variables were represented as a standardized mean difference (SMD), accompanied by a 95% confidence interval (CI). Additionally, we examined the potential targets and plausible pathways associated with the impact of resveratrol on Alzheimer's disease using network pharmacology techniques.

Results: Our meta-analysis comprised five trials involving 271 AD patients, of whom 139 received resveratrol treatment and 132 received placebo treatment. Compared with placebo therapy, resveratrol treatment resulted in a significant improvement in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADAS-ADL) scores (SMD=0.51; 95% CI, 0.24 to 0.78) and cerebrospinal fluid (CSF) Aβ40 (SMD=0.84; 95% CI, 0.21 to 1.47) and plasma Aβ40 levels (SMD=0.43; 95% CI, 0.07 to 0.79). However, the improvement in the resveratrol-treated group compared with the placebo treatment group on the Mini-Mental State Examination (MMSE) score, CSF Aβ42 and plasma Aβ42 levels, and brain volume was not significant. There were no noteworthy statistical variances in the occurrence of adverse effects noted between the two groups. The outcomes of network pharmacology divulged that the principal enriched interaction pathway between resveratrol and Alzheimer's disease is primarily concentrated within the PI3K signaling pathways. Resveratrol's potential key targets for the treatment of AD include MAKP1, HRAS, EGFR, and MAPK2K1.

Conclusion: While having a high safety profile, resveratrol has efficacy in AD patients to a certain extent, and more data are required to validate the efficacy of resveratrol for the treatment of AD in the future. Suppression of the PI3K signaling pathways could hold significant importance in the treatment of AD patients using resveratrol.