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Journal of Neuropsychology Jul 2024Recent research suggests that the retrieval of autobiographical memories among cognitively healthy middle-aged and older adults is sensitive to the Apolipoprotein E ε4...
Recent research suggests that the retrieval of autobiographical memories among cognitively healthy middle-aged and older adults is sensitive to the Apolipoprotein E ε4 (APOE4) allele, a genetic marker that increases the risk of Alzheimer's disease (AD) dementia. However, whether the APOE4-associated alteration in autobiographical memory retrieval encompasses rapid (i.e. direct retrieval) or iterative (i.e. generative retrieval) processes remains unclear. In the present study, 39 APOE4 carriers and 45 non-carriers (ages 60-80) who scored within normal limits on neuropsychological testing were cued to generate specific autobiographical events. We examined group differences in direct and generative retrieval and correlated direct and generative retrieval rates with performance on neuropsychological tests. Direct retrieval rates were lower in the APOE4 carriers compared to non-carriers. Episodic memory positively correlated with direct retrieval rates across the sample, though this relationship became non-significant when factoring in age and sex. There were no significant findings related to successful generative retrieval rates and its efficiency. In summary, compared to non-carriers, cognitively unimpaired middle-aged to older adult APOE4 carriers demonstrated greater difficulty, rapidly reconstructing specific autobiographical events without the support of semantic memory, suggesting that early autobiographical memory retrieval processes demonstrate vulnerability to AD-related risk factors.
PubMed: 38949213
DOI: 10.1111/jnp.12380 -
Cancer Innovation Aug 2024Clinical studies have shown that atherosclerotic cardiovascular disease and cancer often co-exist in the same individual. The present study aimed to investigate the role...
BACKGROUND
Clinical studies have shown that atherosclerotic cardiovascular disease and cancer often co-exist in the same individual. The present study aimed to investigate the role of high-fat-diet (HFD)-induced obesity in the coexistence of the two diseases and the underlying mechanism in apolipoprotein E-knockout (ApoE) mice.
METHODS
Male ApoE mice were fed with a HFD or a normal diet (ND) for 15 weeks. On the first day of Week 13, the mice were inoculated subcutaneously in the right axilla with Lewis lung cancer cells. At Weeks 12 and 15, serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor levels were measured by enzyme-linked immunosorbent assay, and blood monocytes and macrophages were measured by fluorescence-activated cell sorting. At Week 15, the volume and weight of the local subcutaneous lung cancer and metastatic lung cancer and the amount of aortic atherosclerosis were measured.
RESULTS
At Week 15, compared with mice in the ND group, those in the HFD group had a larger volume of local subcutaneous cancer ( = 0.0004), heavier tumors ( = 0.0235), more metastatic cancer in the lungs ( < 0.0001), a larger area of lung involved in metastatic cancer ( = 0.0031), and larger areas of atherosclerosis in the aorta ( < 0.0001). At Week 12, serum LOX-1, serum vascular endothelial growth factor, and proportions of blood monocytes and macrophages were significantly higher in the HFD group than those in the ND group ( = 0.0002, = 0.0029, = 0.0480, and = 0.0106, respectively); this trend persisted until Week 15 ( = 0.0014, = 0.0012, = 0.0001, and = 0.0204).
CONCLUSIONS
In this study, HFD-induced obesity could simultaneously promote progression of lung cancer and atherosclerosis in the same mouse. HFD-induced upregulation of LOX-1 may play an important role in the simultaneous progression of these two conditions via the inflammatory response and VEGF.
PubMed: 38948249
DOI: 10.1002/cai2.127 -
Journal of Alzheimer's Disease : JAD Jun 2024Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite...
BACKGROUND
Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data.
OBJECTIVE
Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features.
METHODS
AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women).
RESULTS
Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status.
CONCLUSIONS
Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.
PubMed: 38943387
DOI: 10.3233/JAD-231321 -
Alzheimer's Research & Therapy Jun 2024Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs).... (Comparative Study)
Comparative Study
BACKGROUND
Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs.
METHODS
Single-molecule enzyme-linked assays were used to quantify Aβ42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4- (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples.
RESULTS
The soluble plasma Aβ42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aβ40, Aβ42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions.
CONCLUSION
Soluble plasma Aβ42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aβ release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aβ and tau need correction by NDEVs for better AD risk identification in CN populations.
Topics: Humans; Alzheimer Disease; Extracellular Vesicles; Biomarkers; Female; Male; Amyloid beta-Peptides; Aged; tau Proteins; Peptide Fragments; Aged, 80 and over; Middle Aged; Cohort Studies; Apolipoprotein E4
PubMed: 38943196
DOI: 10.1186/s13195-024-01508-6 -
Scientific Reports Jun 2024While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer's disease (LOAD), the Apolipoprotein E locus E4 haplotype is still...
While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer's disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59-58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L, HLA-DRA and RANBP3L. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.
Topics: Humans; Alzheimer Disease; Genetic Predisposition to Disease; Apolipoprotein E4; HLA-DR alpha-Chains; Female; Male; Aged; Adaptor Proteins, Signal Transducing; Alleles; Haplotypes; Bayes Theorem; Risk Factors; Nuclear Proteins; Aged, 80 and over
PubMed: 38942763
DOI: 10.1038/s41598-024-65010-7 -
Journal of Lipid Research Jun 2024The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPL) in the development and progression of coronary disease is known, but their influence on...
The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPL) in the development and progression of coronary disease is known, but their influence on extra-coronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extra-coronary vascular disease and incident major adverse limb events (MALE). 446 participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extra-coronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (OR 2.14 95% CI: 1.03, 4.44) and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extra-coronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extra-coronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries. These results lay a foundation in support of studying Lp(a) lowering medications and their effect on limb-related complications.
PubMed: 38942114
DOI: 10.1016/j.jlr.2024.100585 -
Phytomedicine : International Journal... Jun 2024Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism....
BACKGROUND
Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works.
PURPOSE
In this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms.
METHODS
APOE mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant.
RESULTS
APOE mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice.
CONCLUSION
Our study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.
PubMed: 38941813
DOI: 10.1016/j.phymed.2024.155829 -
Poultry Science Jun 2024The late embryonic development of the liver, a major metabolic organ, remains poorly characterized at single cell resolution. Here, we used single-nucleus RNA-sequencing...
The late embryonic development of the liver, a major metabolic organ, remains poorly characterized at single cell resolution. Here, we used single-nucleus RNA-sequencing (snRNA-seq) to characterize the chicken liver cells at 2 embryonic development time points (E14 and D1). We uncovered 8 cell types including hepatocytes, endothelial cells, hepatic stellate cells, erythrocytes, cholangiocytes, kupffer cells, mesothelial cells, and lymphocytes. And we discovered significant differences in the abundance of different cell types between E14 and D1. Moreover, we characterized the heterogeneity of hepatocytes, endothelial cells, and mesenchymal cells based on the gene regulatory networks of each clusters. Trajectory analyses revealed 128 genes associated with hepatocyte development and function, including apolipoprotein genes involved hepatic lipid metabolism and NADH dehydrogenase subunits involved hepatic oxidative phosphorylation. Furthermore, we identified the differentially expressed genes (DEGs) between E14 and D1 at the cellular levels, which contribute to changes in liver development and function. These DEGs were significantly enriched in PPAR signaling pathways and lipid metabolism related pathways. Our results presented the single-cell mapping of chick embryonic liver at late stages of development and demonstrated the metabolic changes across the 2 age stages at the cellular level, which can help to further study the molecular development mechanism of embryonic liver.
PubMed: 38941785
DOI: 10.1016/j.psj.2024.103979 -
NeuroImage. Clinical Jun 2024Advanced age is the most important risk factor for Alzheimer's disease (AD), and carrier-status of the Apolipoprotein E4 (APOE4) allele is the strongest known genetic...
Advanced age is the most important risk factor for Alzheimer's disease (AD), and carrier-status of the Apolipoprotein E4 (APOE4) allele is the strongest known genetic risk factor. Many studies have consistently shown a link between APOE4 and synaptic dysfunction, possibly reflecting pathologically accelerated biological aging in persons at risk for AD. To test the hypothesis that distinct functional connectivity patterns characterize APOE4 carriers across the clinical spectrum of AD, we investigated 128 resting state functional Magnetic Resonance Imaging (fMRI) datasets from the Alzheimer's Disease Neuroimaging Initiative database (ADNI), representing all disease stages from cognitive normal to clinical dementia. Brain region centralities within functional networks, computed as eigenvector centrality, were tested for multivariate associations with chronological age, APOE4 carrier status and clinical stage (as well as their interactions) by partial least square analysis (PLSC). By PLSC analysis two distinct brain activity patterns could be identified, which reflected interactive effects of age, APOE4 and clinical disease stage. A first component including sensorimotor regions and parietal regions correlated with age and AD clinical stage (p < 0.001). A second component focused on medial-frontal regions and was specifically related to the interaction between age and APOE4 (p = 0.032). Our findings are consistent with earlier reports on altered network connectivity in APOE4 carriers. Results of our study highlight promise of graph-theory based network centrality to identify brain connectivity linked to genetic risk, clinical stage and age. Our data suggest the existence of brain network activity patterns that characterize APOE4 carriers across clinical stages of AD.
PubMed: 38941766
DOI: 10.1016/j.nicl.2024.103635 -
Journal of Integrative Neuroscience Jun 2024To determine whether individuals with subjective cognitive decline (SCD) have changes in whole-brain network characteristics and intracerebral node characteristics in...
PURPOSE
To determine whether individuals with subjective cognitive decline (SCD) have changes in whole-brain network characteristics and intracerebral node characteristics in the structural network, and whether there is a difference between SCD with and without Apolipoprotein E4 ().
METHODS
This cross-sectional study included 36 individuals without SCD without (healthy control, HC group), 21 individuals with SCD with (APOEε4+ group), and 33 individuals with SCD without (APOEε4- group). The white matter structural network was constructed using the fractional anisotropy (FA) based deterministic fiber tracking method. Graph theory was used to analyze the whole-brain network characteristics and intracerebral node characteristics of the three groups.
RESULTS
Regarding the whole-brain network characteristics, all three groups exhibited small-worldness in their structural networks. The clustering coefficient (Cp) and local efficiency (Eloc) in the APOEε4+ and APOEε4- groups were significantly lower than in the HC group ( < 0.05), but no significant difference in Cp or Eloc was observed between the APOEε4+ and APOEε4- groups. Regarding intracerebral node characteristics, there were significant differences in some brain regions, mainly the default mode network (DMN), the occipital lobe, the temporal lobe, and subcortical regions. The change in intracerebral node characteristics was different between the APOEε4+ group and the APOEε4- group.
CONCLUSIONS
Individuals with SCD demonstrate changes in whole-brain network characteristics and intracerebral node characteristics in the structural network. Moreover, differences exist between APOEε4+ and APOEε4- individuals.
Topics: Humans; Apolipoprotein E4; White Matter; Male; Female; Cognitive Dysfunction; Cross-Sectional Studies; Aged; Middle Aged; Nerve Net; Diffusion Tensor Imaging; Diagnostic Self Evaluation
PubMed: 38940088
DOI: 10.31083/j.jin2306117