Current Alzheimer research最新文献

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.

Background: Previous studies have linked childhood adversities to dementia risk, yet most studies are cross-sectional in design and utilize retrospective self-reports to assess childhood experiences. These design characteristics make it difficult to establish temporal order and draw firm conclusions.

Objectives: Using a longitudinal design, we sought to determine whether childhood maltreatment predicts dementia risk factors in middle adulthood.

Methods: Data have been obtained from a prospective cohort design study of children with documented cases of childhood maltreatment (ages 0-11 years at case identification) and demographically matched controls who were followed up and interviewed in middle adulthood. Outcomes were assessed through a medical examination and interview, and 807 of the cases that included blood collection at mean age 41. Dementia risk were investigated using 11 potentially modifiable risk factors.

Results: Compared to controls, individuals with histories of childhood maltreatment had a higher risk of low educational attainment, low social contact, smoking, and clinical depression, and a higher total number of dementia risk factors. In general, childhood maltreatment predicted a higher risk of dementia for females, males, and Black and White participants. Black maltreated participants had a greater risk for traumatic brain injury compared to Black controls. Physical abuse, sexual abuse, and neglect, each predicted a higher number of dementia risk factors in mid-life.

Conclusion: These findings provide evidence that childhood maltreatment increases the risk for dementia in mid-life and has a demonstrable impact lasting over 30 years. Reducing the prevalence of mid-life dementia risk factors could reduce the risk of later-life dementia.

Background: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.

Methods: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.

Results: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound.

Conclusion: This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.

Background and objective: Recent evidence suggests that blood-based biomarkers might be useful for Alzheimer's disease (AD). Among them, we intend to investigate whether neurofilament light (NfL) and multimer detection system-oligomeric Aβ (MDS-OAβ) values can be useful in screening, predicting, and monitoring disease progression and how the relationship between NfL and MDS-OAβ values changes.

Methods: Eighty participants with probable AD dementia, 50 with mild cognitive impairment (MCI), and 19 with subjective cognitive decline (SCD) underwent baseline and follow-up evaluations of the Mini-Mental Status Examination (MMSE) and both plasma biomarkers.

Results: Baseline MDS-OAß (p = 0.016) and NfL (p = 0.002) plasma concentrations differed significantly among groups, but only NfL correlated with baseline MMSE scores (r = -0.278, p = 0.001). In follow-up, neither correlated with MMSE changes overall. However, in SCD and MCI participants (n = 32), baseline MDS-OAß correlated with follow-up MMSE scores (r = 0.532, p = 0.041). Linear regression revealed a relationship between baseline MDS-OAβ and follow-up MMSE scores. In SCD and MCI participants, plasma NfL changes correlated with MMSE changes (r = 0.564, p = 0.028).

Conclusion: This study shows that only in participants with SCD and MCI, not including AD dementia, can MDS-OAß predict the longitudinal cognitive decline measured by follow-up MMSE. Changes of NfL, not MDS-OAß, parallel the changes of MMSE. Further studies with larger samples and longer durations could strengthen these results..

Background: The development of biomarkers that are easy to collect, process, and store is a major goal of research on current Alzheimer's Disease (AD) and underlies the growing interest in plasma biomarkers. Biomarkers with these qualities will improve diagnosis and allow for better monitoring of therapeutic interventions. However, blood collection strategies have historically differed between studies. We examined the ability of various ultrasensitive plasma biomarkers to predict cerebral amyloid status in cognitively unimpaired individuals when collected using acid citrate dextrose (ACD). We then examined the ability of these biomarkers to predict cognitive impairment independent of amyloid status.

Methods: Using a cross-sectional study design, we measured amyloid beta 42/40 ratio, pTau-181, neurofilament-light, and glial fibrillary acidic protein using the Quanterix Simoa® HD-X platform. To evaluate the discriminative accuracy of these biomarkers in determining cerebral amyloid status, we used both banked plasma and 18F-AV45 PET cerebral amyloid neuroimaging data from 140 cognitively unimpaired participants. We further examined their ability to discriminate cognitive status by leveraging data from 42 cognitively impaired older adults. This study is the first, as per our knowledge, to examine these specific tests using plasma collected using acid citrate dextrose (ACD), as well as the relationship with amyloid PET status.

Results: Plasma AB42/40 had the highest AUC (0.833, 95% C.I. 0.767-0.899) at a cut-point of 0.0706 for discriminating between the two cerebral amyloid groups (sensitivity 76%, specificity 78.5%). Plasma NFL at a cut-point of 20.58pg/mL had the highest AUC (0.908, 95% CI 0.851- 0.966) for discriminating cognitive impairment (sensitivity 84.8%, specificity 89.9%). The addition of age and apolipoprotein e4 status did not improve the discriminative accuracy of these biomarkers.

Conclusion: Our results suggest that the Aβ42/40 ratio is useful in discriminating clinician-rated elevated cerebral amyloid status and that NFL is useful for discriminating cognitive impairment status. These findings reinforce the growing body of evidence regarding the general utility of these biomarkers and extend their utility to plasma collected in a non-traditional anticoagulant.

Objectives: Evaluate the acceptability and efficacy of an online dementia prevention intervention based on a cognitive behavioral shared decision-making model.

Materials and methods: This was an unblinded pilot study in which participants were randomly assigned to one of two treatment groups. This study was carried out remotely via telephone, video conferencing, and online data collection. Eighteen English-speaking persons 40 years of age and older interested in developing more brain-healthy lifestyles. Both groups received 12 weekly sessions on lifestyle factors related to cognitive decline. The treatment-as-usual (TAU) group received the information and was encouraged to make lifestyle changes. The cognitive behavioral shared decision- making model (CBSDM) group received structured weekly sessions with support for evidence- informed personal goal choices and behavior change strategies. Primary outcome measures were the Alzheimer's Disease Risk Inventory and the Memory Self-Efficacy and Dementia Knowledge Assessment Scales. Participants reported brain health activities during the first, sixth, and 12th weeks of the study.

Results: No significant between-group changes were seen in the three primary outcome measures. The intervention was viewed positively by participants, who all said they would participate in it again. Participants in the CBSDM group showed increases in knowledge of dementia risk factors and exercise. Other outcomes were consistent with moderate to large effect sizes for both groups.

Conclusion: An online intervention providing psychoeducation and behavior change support was viewed positively by older adults. Results provide preliminary support for the CBSDM intervention's efficacy in promoting brain health in older adults.

Clinical trial registration number: NCT04822129.