Search

Background: Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear. Methods: We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results: MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P < 0.005). Conclusions: Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation. [ABSTRACT FROM AUTHOR]

A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression. [ABSTRACT FROM AUTHOR]

A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer's disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka "nucleolar satellite") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer's, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases. [ABSTRACT FROM AUTHOR]

Lipid metabolism and oxidative stress are key mechanisms in Alzheimer's disease (AD). The link between plasma lipid metabolites and oxidative stress in AD patients is poorly understood. This study was to identify markers that distinguish AD and amnestic mild cognitive impairment (aMCI) from NC, and to reveal potential links between lipid metabolites and oxidative stress. We performed non‐targeted lipid metabolism analysis of plasma from patients with AD, aMCI, and NC using LC–MS/MS. The plasma malondialdehyde (MDA), glutathione peroxidase (GSH‐Px), and superoxide dismutase (SOD) levels were assessed. We found significant differences in lipid metabolism between patients with AD and aMCI compared to those in NC. AD severity is associated with lipid metabolites, especially TG (18:0_16:0_18:0) + NH4, TG (18:0_16:0_16:0) + NH4, LPC(16:1e)‐CH3, and PE (20:0_20:4)‐H. SPH (d16:0) + H, SPH (d18:1) + H, and SPH (d18:0) + H were high‐performance markers to distinguish AD and aMCI from NC. The AUC of three SPHs combined to predict AD was 0.990, with specificity and sensitivity as 0.949 and 1, respectively; the AUC of three SPHs combined to predict aMCI was 0.934, with specificity and sensitivity as 0.900, 0.981, respectively. Plasma MDA concentrations were higher in the AD group than in the NC group (p = 0.003), whereas plasma SOD levels were lower in the AD (p < 0.001) and aMCI (p = 0.045) groups than in NC, and GSH‐Px activity were higher in the AD group than in the aMCI group (p = 0.007). In addition, lipid metabolites and oxidative stress are widely associated. In conclusion, this study distinguished serum lipid metabolism in AD, aMCI, and NC subjects, highlighting that the three SPHs can distinguish AD and aMCI from NC. Additionally, AD patients showed elevated oxidative stress, and there are complex interactions between lipid metabolites and oxidative stress. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) is defined as inter-stage between normal cognitive aging and major neurocognitive disorder (MND). This state of decay is a crucial factor in treatment to prevent the progression to MND. In this study, our group developed a virtual screening process to evaluate 2568 phytochemical compounds against 5 key proteins associated with MCI and MND. As a result, two potential candidates were identified: carpaine, found in Carica papaya leaves, and punicalagin, present in Punica granatum. A model of cognitive impairment (CI) was developed in 10-month-old male Sprague Dawley rats by administering aluminum chloride (AlCl3) at a dose of 100 mg/kg/day for 30 days. After AlCl3 administration period, one of the groups received carpaine and punicalagin in a phytochemical extract (PE) by oral gavage for 30 days. Novel object recognition test (NOR) was assessed at three different time points (T1 — before CI, T2 — after CI, and T3 — after PE treatment). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were identified in the hippocampus of rats at the end of the study period. After administration of AlCl3, a reduction in discrimination index vs control rats (CI = 0.012 ± 0.08 vs Control = 0.076 ± 0.03), was observed. After phytochemical extract treatment, a significant increase in discrimination index values was observed in the PE group 0.4643 ± 0.13 vs CI group 0.012 ± 0.08. Additionally, the evaluation of immunohistochemistry showed an increase in GFAP positivity in the hippocampus of the CI groups, while a slight decrease was observed in the PE group. This work addressed a comprehensive methodology that utilized in silico tools to identify phytochemical compounds (carpaine and punicalagin) as potential candidates for affecting key proteins in CI. The phytochemical extract containing carpaine and punicalagin resulted in a trend in the decrease of GFAP expression in the hippocampus and improved recognition memory in rats with CI induced by age and AlCl3 administration. [ABSTRACT FROM AUTHOR]

Background: Pyroptosis plays an important role in the pathological process of ischemic stroke (IS). However, the exact mechanism of pyroptosis remains unclear. This paper aims to reveal the key molecular markers associated with pyroptosis in IS. Methods: We used random forest learning, gene set variation analysis, and Pearson correlation analysis to screen for biomarkers associated with pyroptosis in IS. Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen and glucose deprivation/reoxygenation (OGD/R) models were constructed in vitro and in vivo. Cells were transfected with an Annexin A3 silencing (si-ANXA3) plasmid to observe the effects of ANXA3 on OGD/R + lipopolysaccharides (LPS)-induced pyroptosis. qRT‒PCR and western blotting were used to detect the expression of potential biomarkers and pyroptotic pathways. Results: Samples from a total of 170 IS patients and 109 healthy individuals were obtained from 5 gene expression omnibus databases. Thirty important genes were analyzed by random forest learning from the differentially expressed genes. Then, we investigated the relationship between the above genes and the pyroptosis score, obtaining three potential biomarkers (ANXA3, ANKRD22, ADM). ANXA3 and ADM were upregulated in the MCAO/R model, and the fold difference in ANXA3 expression was greater. Pyroptosis-related factors (NLRP3, NLRC4, AIM2, GSDMD-N, caspase-8, pro-caspase-1, cleaved caspase-1, IL-1β, and IL-18) were upregulated in the MCAO/R model. Silencing ANXA3 alleviated the expression of pyroptosis-related factors (NLRC4, AIM2, GSDMD-N, caspase-8, pro-caspase-1, cleaved caspase-1, and IL-18) induced by OGD/R + LPS or MCAO/R. Conclusion: This study identified ANXA3 as a possible pyroptosis-related gene marker in IS through bioinformatics and experiments. ANXA3 could inhibit pyroptosis through the NLRC4/AIM2 axis. [ABSTRACT FROM AUTHOR]

In the relevant study by Boulares and colleagues, the importance of a multicomponent physical activity program in improving balance skills and leading to falling risk and fear reduction in older adults with mild cognitive impairment (MCI) is highlighted, despite the lack of cognitive effects. Given this apparent discrepancy between "body" and "mind" in MCI rehabilitation, the present commentary faces and discusses these findings within the existing literature and poses the question whether there were actually no cognitive results or if the program design and evaluation tool used were not sensitive enough to detect them, at least at this stage. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a complex psychiatric disease characterized by alternating mood episodes. As for any other psychiatric illness, currently there is no biochemical test that is able to support diagnosis or therapeutic decisions for BD. In this context, the discovery and validation of biomarkers are interesting strategies that can be achieved through proteomics and metabolomics. In this descriptive review, a literature search including original articles and systematic reviews published in the last decade was performed with the objective to discuss the results of BD proteomic and metabolomic profiling analyses and indicate proteins and metabolites (or metabolic pathways) with potential clinical value. A large number of proteins and metabolites have been reported as potential BD biomarkers; however, most studies do not reach biomarker validation stages. An effort from the scientific community should be directed toward the validation of biomarkers and the development of simplified bioanalytical techniques or protocols to determine them in biological samples, in order to translate proteomic and metabolomic findings into clinical routine assays. [ABSTRACT FROM AUTHOR]

The article emphasizes the comprehensive management of dementia in family medicine, covering types, diagnosis, pharmacotherapy, lifestyle interventions and support for patients and caregivers. It underscores the increasing prevalence of dementia with advancing age and encourages feedback for continuous improvement.

Aim: Proinflammatory cytokines such as interleukin‐6 (IL‐6) and IL‐17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL‐17A, induces impairment in sensorimotor gating in mice. We also examined whether IL‐17A administration affects GSK3α/β protein level or phosphorylation in the striatum. Methods: Recombinant mouse IL‐17A (low‐dose: 0.5 ng/mL and high‐dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub‐chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL‐17A administration. We evaluated the effect of IL‐17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis. Results: Administration of IL‐17A induced significant PPI deterioration. Low‐dose of IL‐17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low‐dose IL‐17A administration group. Conclusion: We demonstrated for the first time that sub‐chronic IL‐17A administration induced PPI disruption and that IL‐17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL‐17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia and bipolar disorder are disorders characterized by alterations in cellular and molecular mechanisms. Annexin A3 (ANXA3) has various effects on neural mechanisms and membrane phospholipid function and both mechanisms are thought to be associated with psychotic disorders. Our study consisted of 93 schizophrenia and bipolar disorder and 52 healthy controls. ANXA3 was analyzed by enzyme-linked immunosorbent assay (ELISA). ANXA3 levels were significantly different between the groups (p<0.001). ANXA3 levels of the control group were higher than ANXA3 levels of schizophrenia and bipolar disorder groups (p<0.001, p<0.001). The ANXA3 levels of the bipolar group were higher than the ANXA3 levels of the schizophrenia group (p<0.001). Laboratory levels of B12, folate, vitamin D, glucose, urea, creatinine, prothrombin time (PT), gamma-glutamyl transferase and lactate dehydrogenase were compared between the groups. B12 levels of the schizophrenia group were lower than B12 levels of bipolar and control groups (p=0.05, p<0.001). Creatinine levels of the schizophrenia group were higher than the creatinine levels of the healthy group (p<0.05). According to posthoc test results, PT levels of the schizophrenia group were higher than PT levels of the healthy group (p<0.05). In line with these findings, we suggest that ANXA3 protein deficiency may have an important role in the physiopathology of schizophrenia and bipolar disorder and may be used as a biomarker in the diagnosis of some psychotic disorders. [ABSTRACT FROM AUTHOR]

The S100 proteins family is known to affect neuroinflammation and astrocyte activation, which have been suggested to be contributors to the pathogenesis of schizophrenia. We conducted a systematic meta-analysis of S100 genes differential expression in postmortem samples of patients with schizophrenia vs. healthy controls, following the commonly used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Twelve microarray datasets met the inclusion criteria (overall 511 samples, 253 schizophrenia and 258 controls were analyzed). Nine out of 21 genes were significantly up-regulated or with tendency for up-regulation. A per-sample fold change analysis indicated that the S100 genes' up-regulation was concentrated in a subgroup of the patients. None of the genes have been found to be down-regulated. ANXA3, which encodes Annexin 3 protein and was associated with neuroinflammation, was up-regulated and positively correlated with the S100 genes' expression pattern. In addition, astrocytes and endothelial cell markers were significantly correlated with S100A8 expression. S100 correlation with ANXA3 and endothelial cell markers suggests that the up-regulation we detected reflects increased inflammation. However, it might also reflect astrocytes abundance or activation. The fact that S100 proteins were shown to be up-regulated in blood samples and other body fluids of patients with schizophrenia suggests a potential role as biomarkers, which might help disease subtyping, and the development of etiological treatments for immune dysregulation in schizophrenia. [ABSTRACT FROM AUTHOR]

Aims: Alzheimer's disease (AD) is a neurodegenerative disease with challenging early diagnosis and effective treatments due to its complex pathogenesis. AD patients are often diagnosed after the appearance of the typical symptoms, thereby delaying the best opportunity for effective measures. Biomarkers could be the key to resolving the challenge. This review aims to provide an overview of application and potential value of AD biomarkers in fluids, including cerebrospinal fluid, blood, and saliva, in diagnosis and treatment. Methods: A comprehensive search of the relevant literature was conducted to summarize potential biomarkers for AD in fluids. The paper further explored the biomarkers' utility in disease diagnosis and drug target development. Results: Research on biomarkers mainly focused on amyloid‐β (Aβ) plaques, Tau protein abnormal phosphorylation, axon damage, synaptic dysfunction, inflammation, and related hypotheses associated with AD mechanisms. Aβ42, total Tau (t‐Tau), and phosphorylated Tau (p‐Tau), have been endorsed for their diagnostic and predictive capability. However, other biomarkers remain controversial. Drugs targeting Aβ have shown some efficacy and those that target BACE1 and Tau are still undergoing development. Conclusion: Fluid biomarkers hold considerable potential in the diagnosis and drug development of AD. However, improvements in sensitivity and specificity, and approaches for managing sample impurities, need to be addressed for better diagnosis. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Attenuated Psychosis Syndrome (APS) impacts functioning and predicts increased risk of psychosis. Risk for developing APS itself has received minimal attention. Knowledge of familial and environmental contributions to APS symptoms would advance understanding of APS and risk for psychosis. As an initial step, this report presents the first data on APS symptoms in family members of APS patients. Study Design This study utilized a discordant sibling-pair family study design. The Structured Interview for Psychosis-risk Syndromes (SIPS) was administered to 17 APS probands and 26 non-APS biological siblings. Probands and siblings were compared on positive, negative, disorganized, and general SIPS symptom scales and factors derived from those scales. Study Results There was significantly greater symptom severity in probands compared to siblings on nine of 19 SIPS scales. Negative/anxiety, functioning, and positive symptom factors were identified. Probands showed significantly greater severity than siblings on the negative/anxiety and positive factors. Elevated pathology on the negative/anxiety factor best differentiated between probands and siblings, over and above the contribution of the positive factor. No difference was found for the functioning factor. Conclusions Results support the importance of non-familial effects on risk for APS and suggest differences in familial contribution to APS symptoms. Understanding the relative contribution of familial and environmental effects on APS symptoms may reveal important differences among APS patients, with implications for risk characterization, symptom course, and treatment selection. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal disorders (FTD) are the consequence of impairment to neurons in the frontal and temporal lobes of the brain. Also, no definitive treatment has been found for FTD. Cannabinoid products can be used to manage treatment-resistant behavioral variants of Frontotemporal dementia (bvFTD). Case presentation: We describe the case of 34 years old male with two years of marijuana abuse. At first, he presented with symptoms of apathy and bizarre behavior, which became more severe, and led to disinhibition. The clinical symptoms and imaging findings made FTD probable for him, which was very interesting to report. Conclusions: While cannabis has demonstrated potential in managing behavioral and mental symptoms of dementia, the presented case highlights the profound impact of cannabis consumption on brain structure and chemistry, including the potential for neurodegenerative disorders like FTD. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a risk factor for Alzheimer's disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n = 12), MCI with remitted MDD (MDD+MCI) (n = 12), and remitted MDD alone (MDD) (n = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in MCI patients with AD(-) biomarkers. [ABSTRACT FROM AUTHOR]

The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer's disease (AD). To provide novel insights into the roles of astrocytes in the pathophysiology of AD, we performed a quantitative ultrastructural characterization of their intracellular contents and parenchymal interactions in an aged mouse model of AD pathology, as aging is considered the main risk factor for developing AD. We compared 20-month-old APP-PS1 and age-matched C57BL/6J male mice, among the ventral hippocampus CA1 strata lacunosum-moleculare and radiatum, two hippocampal layers severely affected by AD pathology. Astrocytes in both layers interacted more with synaptic elements and displayed more ultrastructural markers of increased phagolysosomal activity in APP-PS1 versus C57BL6/J mice. In addition, we investigated the ultrastructural heterogeneity of astrocytes, describing in the two examined layers a dark astrocytic state that we characterized in terms of distribution, interactions with AD hallmarks, and intracellular contents. This electron-dense astrocytic state, termed dark astrocytes, was observed throughout the hippocampal parenchyma, closely associated with the vasculature, and possessed several ultrastructural markers of cellular stress. A case study exploring the hippocampal head of an aged human post-mortem brain sample also revealed the presence of a similar electron-dense, dark astrocytic state. Overall, our study provides the first ultrastructural quantitative analysis of astrocytes among the hippocampus in aged AD pathology, as well as a thorough characterization of a dark astrocytic state conserved from mouse to human. [ABSTRACT FROM AUTHOR]

Purpose: The plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker of cerebral microbleeds (CMBs) and may be related to the occurrence, development, and prognosis of cognitive impairment. The present study aimed to investigate the impact of plasma Lp-PLA2 level on the cognitive impairment in patients with CMBs. Methods: In this study, 213 patients with CMBs confirmed by 3.0 T brain magnetic resonance imaging (MRI) were analyzed. Lp-PLA2 levels were determined by magnetic particle chemiluminescence immunoassay technology, and cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The cognitive functions of patients with CMBs were divided into three groups according to the MoCA scale, including normal cognition (NC), mild cognitive impairment (MCI), and moderate-severe cognitive impairment (MSCI). Clinical, laboratory and radiological data of the three groups were analysed. The relationship between plasma Lp-PLA2 and MoCA score in patients with CMBs was investigated through rank correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Lp-PLA2. Results: CMBs were detected in 213 (30.2%) of 705 patients who underwent 3.0 T MRI. Multiple comparisons showed that plasma Lp-PLA2 in patients with CMBs with normal cognitive scores was significantly lower than that in the other two groups with cognitive impairment (p < 0.05). In the single factor correlation analysis, high level of plasma Lp-PLA2 was negatively correlated with the decrease of MoCA score in patients with CMBs (r =− 0.389, p < 0.01). Multivariate regression analysis showed that high plasma Lp-PLA2 was an independent risk factor for a low MoCA score in patients with CMBs (odds ratio [OR]=1.014; 95% confidence interval [CI], 1.002– 1.026; p=0.025). Conclusion: A high level of plasma Lp-PLA2 is positively correlated with the generation of cognitive impairment in patients with CMBs and negatively correlated with the degree of impairment. Plasma Lp-PLA2 is an important indicator of cognitive impairment in patients with CMBs and may provide a therapeutic target for preventing CMB-induced cognitive impairment. [ABSTRACT FROM AUTHOR]

To explore potential molecular mechanisms and novel biomarkers of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The mRNA expression datasets GSE63060 and GSE63061 and the miRNA expression dataset GSE120584 were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) and miRNA (DEmiRs) were identified in the normal, MCI, and AD groups. Mfuzz clustering and weighted correlation network analyses (WGCNA) were conducted, followed by pathway and functional enrichment analyses and miRNA-mRNA network construction. Furthermore, phenotypic correlation analysis and experimental verification were performed on key DEGs and DEmiRs. In total, 3,000 intersected DEGs from GSE63060/GSE63061 and 817 DEmiRs from GSE120584 were obtained. Mfuzz and WGCNA analyses revealed 106 DEGs including ribosomal protein L11 (RPL11) and 28 DEmiRs including miR-6764-5p. These DEGs and DEmiRs were mainly enriched in pathways like Ribosome. Moreover, 5 key DEGs including cytohesin 4 (CYTH4) and 6 crucial DEmiRs including miR-6734-3p were identified by miRNA–mRNA interaction network analysis. Phenotypic correlation analysis showed that CYTH4 and miR-6734-3p were correlated with patients' age. The results of quantitative polymerase chain reaction analysis confirmed that RPL11 expression was significantly downregulated in the MCI and AD groups compared to that in the normal group, while the expression of CYTH4, miR-6764-5p, and miR-6734-3p was remarkably upregulated in the MCI and AD groups. miR-6764-5p might contribute to MCI and AD by targeting RPL11 in the ribosome pathway. Therefore, miR-6734-3p and its target mRNA CYTH4 might be used as novel biomarkers for MCI and AD. [ABSTRACT FROM AUTHOR]

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals. [ABSTRACT FROM AUTHOR]

The automated magnetic resonance imaging (MRI) processing techniques are gaining more importance in Alzheimer disease (AD) recognition, because it effectively diagnosis the pathology of the brain. Currently, computer aided diagnosis based on image analysis is an emerging tool to support AD diagnosis. In this research study, a new system is developed for enhancing the performance of AD recognition. Initially, the brain images were acquired from three online datasets and one real-time dataset such as AD Neuroimaging Initiative (ADNI), Minimal Interval Resonance Imaging in AD (MIRIAD), and Open Access Series of Imaging Studies (OASIS) and National Institute of Mental Health and Neuro Sciences (NIMHANS). Then, adaptive histogram equalization (AHE) and grey wolf optimization based clustering algorithm (GWOCA) were applied for denoising and segmenting the brain tissues; grey matter (GM), cerebro-spinal fluid (CSF), and white matter (WM) from the acquired images. After segmentation, the feature extraction was performed by utilizing dual tree complex wavelet transform (DTCWT), local ternary pattern (LTP) and Tamura features to extract the feature vectors from the segmented brain tissues. Then, ReliefF methodology was used to select the active features from the extracted feature vectors. Finally, the selected active feature values were classified into three classes [AD, normal and mild cognitive impairment (MCI)] utilizing deep neural network (DNN) classifier. From the simulation result, it is clear that the proposed framework achieved good performance in disease classification and almost showed 2.2–6% enhancement in accuracy of all four datasets. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) acts as a complex and burdensome disease, in which the functional outcome can be validly predicted by cognitive impairment, as one of the core features. However, there still lack considerable markers of cognitive deficits in SCZ. Based on metabolomics, it is expected to identify different metabolic characteristics of SCZ with cognitive impairment. In the present study, 17 SCZ patients with cognitive impairment (CI), 17 matched SCZ patients with cognitive normal (CN), and 20 healthy control subjects (HC) were recruited, whose plasma metabolites were measured using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The result of metabolic profiling indicated the identification of 46 differentially expressed metabolites between HC, CN, and CI groups, with 7 differentially expressed metabolites between CN and CI groups. Four differential metabolites (imidazolepropionic acid, Homoserine, and Aspartic acid) were repeatedly found in both screenings, by which the formed biomarker panel could discriminate SCZ with cognitive impairment from matched patients (AUC=0.974) and health control (AUC=0.841), respectively. Several significant metabolic pathways were highlighted in pathway analysis, involving Alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, and Citrate cycle (TCA cycle). In this study, several differentially expressed metabolites were identified in SCZ with cognitive impairment, providing novel insights into clinical treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The relationship between diabetes mellitus and neurodegenerative disorders has been of great interest. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine in which a variety of signaling cascades are activated through it. MIF has been involved in the pathogenesis of several diseases and can predict early pre-symptomatic stages of neurodegeneration in diabetic patients.Objective: To investigate whether serum MIF could predict brain neurodegeneration at the early pre-symptomatic stages in diabetic patients.Methods: We examined adults with type 2 diabetes mellitus and compared with normal control adults using a short form of the IQCODE and biochemical examination, including assessment of HA1C, fasting blood glucose, lipid profile, and MIF which was measured by ELISA technique. Correlations between parameters were studied. Computational PathLinker bioinformatic tool was used to search for potential pathway reconstructions for the insulin/amyloid-β/MIF signaling.Results: We demonstrated that MIF level was increased in the serum at the early pre-symptomatic stages of neurodegenerative disorder in diabetic patients. In addition, network analysis demonstrates that insulin receptor substrate 1 can ameliorate amyloid-β protein precursor through COP9 signalosome complex subunit 5 that enhances MIF elevation.Conclusion: Diagnosis processes could not be used as routine examinations for still pre-symptomatic neurodegenerative disorders. This may be due to the time constraints and the heavy dependence on the physician's experience. Therefore, serum MIF level could predict brain neurodegeneration at the early pre-symptomatic stages in diabetic patients which may support its potential utility as a clinically useful biomarker. [ABSTRACT FROM AUTHOR]

Depression is common in older individuals and is associated with high disability and increased mortality, yet the factors predicting late-life depression (LLD) are poorly understood. The relationship between of depressive disorder, age- and disease-related processes have generated pathogenic hypotheses and provided new treatment options. LLD syndrome is often related to a variety of vascular mechanisms, in particular hypertension, cerebral small vessel disease, white matter lesions, subcortical vascular impairment, and other processes (e.g., inflammation, neuroimmune regulatory dysmechanisms, neurodegenerative changes, amyloid accumulation) that may represent etiological factors by affecting frontolimbic and other neuronal networks predisposing to depression. The "vascular depression" hypothesis suggests that cerebrovascular disease (CVD) and vascular risk factors may predispose, induce or perpetuate geriatric depressive disorders. It is based on the presence of various cerebrovascular risk factors in many patients with LLD, its co-morbidity with cerebrovascular lesions, and the frequent development of depression after stroke. Other findings related to vascular depression are atrophy of the medial temporal cortex or generalized cortical atrophy that are usually associated with cognitive impairment. Other pathogenetic hypotheses of LLD, such as metabolic or inflammatory ones, are briefly discussed. Treatment planning should consider there may be a modest response to antidepressants, but several evidence-based and novel treatment options for LLD exist, such as electroconvulsive therapy, transcranial magnetic stimulation, neurobiology-based psychotherapy, as well as antihypertension and antiinflammatory drugs. However, their effectiveness needs further investigation, and new methodologies for prevention and treatment of depression in older individuals should be developed. [ABSTRACT FROM AUTHOR]

Background: Platelet proteins may be associated with Alzheimer's disease (AD) pathology.Objective: To investigate the relationship between platelet proteins and cerebrospinal fluid (CSF) biomarkers of AD and cognition in individuals with memory decline to identify effective screening methods for detecting the early stages of the disease.Methods: We classified 68 participants with subjective memory decline according to the ATN framework determined by CSF amyloid-β (A), CSF p-tau (T), and t-tau (N). All participants underwent Mini-Mental State Examination (MMSE) and platelet-related protein content testing.Results: Eighteen participants had normal AD biomarkers (NCs), 24 subjects had non-AD pathologic changes (non-AD), and 26 subjects fell within the Alzheimer's continuum (AD). The platelet amyloid-β protein precursor (AβPP) ratio in the AD group was significantly lower than in the non-AD and NCs groups, and positively correlated with MMSE scores and CSF amyloid-β42 level, which could affect MMSE scores through CSF amyloid-β42. Levels of platelet phosphorylated-tau 231 and ser396/404 phosphorylated tau were elevated in both AD and non-AD compared to NCs. Additionally, the receiver operating characteristic analysis demonstrated that the platelet AβPP ratio was a sensitive identifier for differentiating the AD from NCs (AUC = 0.846) and non-AD (AUC = 0.768). And ser396/404 phosphorylated tau could distinguish AD from NCs.Conclusion: Our study was the first to find an association between platelet AβPP ratio and CSF biomarkers of AD, which contribute to the understanding of the peripheral changes in AD. These findings may help to discover potential feasible and effective screening tools for AD. [ABSTRACT FROM AUTHOR]

Introduction: Increased systemic oxidative stress is common in schizophrenia (SZ) patients. NADPH-oxidase 4 (NOX4) is the cell oxidoreductase, catalyzing the hydrogen peroxide formation. Presumably, NOX4 is the main oxidative stress factor in a number of diseases such as cardiovascular diseases and cancer. We hypothesized that NOX4 may be involved in the oxidative stress development caused by the disease in the schizophrenic patients' peripheral blood lymphocytes (PBL). Materials and methods: The SZ group included 100 patients (68 men and 32 women aged 28 ± 11 years). The control group included 60 volunteers (35 men and 25 women aged 25 ± 12 years). Flow cytometry analysis (FCA) was used for DNA damage markers (8-oxodG, ɣH2AX), pro- and antiapoptotic proteins (BAX1 and BCL2) and the master-regulator of anti-oxidant response NRF2 detection in the lymphocytes of the untreated SZ patients (N = 100) and the healthy control (HC, N = 60). FCA and RT-qPCR were used for NOX4 and RNANOX4 detection in the lymphocytes. RT-qPCR was used for mtDNA quantitation in peripheral blood mononuclear cells. Cell-free DNA concentration was determined in blood plasma fluorimetrically. Results: 8-oxodG, NOX4, and BCL2 levels in the PBL in the SZ group were higher than those in the HC group (p < 0.001). ɣH2AX protein level was increased in the subgroup with high 8-oxodG (p<0.02) levels and decreased in the subgroup with low 8-oxodG (p <0.0001) levels. A positive correlation was found between 8-oxodG, ɣH2AX and BAX1 levels in the SZ group (p <10−6). NOX4 level in lymphocytes did not depend on the DNA damage markers values and BAX1 and BCL2 proteins levels. In 15% of PBL of the HC group a small cellular subfraction was found (5–12% of the total lymphocyte pool) with high DNA damage level and elevated BAX1 protein level. The number of such cells was maximal in PBL samples with low NOX4 protein levels. Conclusion: Significant NOX4 gene expression was found a in SZ patients' lymphocytes, but the corresponding protein is probably not a cause of the DNA damage. [ABSTRACT FROM AUTHOR]

Since the establishment of the biomarker-based A-T-N (Amyloid/Tau/Neurodegeneration) framework in Alzheimer's disease (AD), the diagnosis of AD has become more precise, and cerebrospinal fluid tests and positron emission tomography examinations based on this framework have become widely accepted. However, the A-T-N framework does not encompass the whole spectrum of AD pathologies, and problems with invasiveness and high cost limit the application of the above diagnostic methods aimed at the central nervous system. Therefore, we suggest the addition of an "X" to the A-T-N framework and a focus on peripheral biomarkers in the diagnosis of AD. In this review, we retrospectively describe the recent progress in biomarkers based on the A-T-N-X framework, analyze the problems, and present our perspectives on the diagnosis of AD. [ABSTRACT FROM AUTHOR]

Despite the availability of over 30 antiseizure medications (ASMs), there is no "one size fits it all," so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5‐hydroxytryptamine, 5‐HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5‐HT. There are 14 different 5‐HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5‐HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each "5‐HT subtype" separately and its relation to "epilepsy or seizures." Most research underlines the antiseizure activity of 5‐HT1A,1D,2A,2C,3 agonism and 5‐HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5‐HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB1 and CB2) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB1 expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB2 upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB1 and CB2 have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A2 activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is a central component of Alzheimer's disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum.Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum.Methods: We collected serum from 49 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument.Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients.Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort. [ABSTRACT FROM AUTHOR]

Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits. The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms. [ABSTRACT FROM AUTHOR]

The exact molecular mechanisms associated with Alzheimer's disease (AD) pathology continue to represent a mystery. In the past decades, comprehensive data were generated on the involvement of different signaling pathways in the AD pathogenesis. However, the utilization of signaling pathways as potential targets for the development of drugs against AD is rather limited due to the immense complexity of the brain and intricate molecular links between these pathways. Therefore, finding a correlation and cross‐talk between these signaling pathways and establishing different therapeutic targets within and between those pathways are needed for better understanding of the biological events responsible for the AD‐related neurodegeneration. For example, autophagy is a conservative cellular process that shows link with many other AD‐related pathways and is crucial for maintenance of the correct cellular balance by degrading AD‐associated pathogenic proteins. Considering the central role of autophagy in AD and its interplay with many other pathways, the finest therapeutic strategy to fight against AD is the use of autophagy as a target. As an essential step in this direction, this comprehensive review represents recent findings on the individual AD‐related signaling pathways, describes key features of these pathways and their cross‐talk with autophagy, represents current drug development, and introduces some of the multitarget beneficial approaches and strategies for the therapeutic intervention of AD. [ABSTRACT FROM AUTHOR]

Pre-pregnancy overweight and obesity, depending on maternal nutrition and metabolic state, can influence fetal, neonatal, and long-term offspring health, regarding cardio-metabolic, respiratory, immunological, and cognitive outcomes. Thus, maternal weight can act, through mechanisms not fully understood, on the physiology and metabolism of some fetal organs and tissues, to adapt themselves to the intrauterine environment and nutritional reserves. These effects can occur by modulating gene expression, neonatal microbiome, and through breastfeeding. In this paper, we investigated the potential effects of metabolites found altered in breast milk (BM) of overweight/obese mothers, through an extensive review of metabolomics studies, and the potential short and long-term clinical effects in the offspring, especially overweight, glucose homeostasis, insulin resistance, oxidative stress, infections, immune processes, neurodevelopment. Metabolomics seems the ideal tool to investigate BM variation depending on maternal or fetal/neonatal factors. In particular, BM metabolome alterations according to maternal conditions were recently pointed out in cases of gestational diabetes, preeclampsia, intrauterine growth restriction and maternal overweight/obesity. In our opinion, even if BM is the food of choice in neonatal nutrition, the deepest comprehension of its composition in overweight/obese mothers could allow targeted supplementation, to improve offspring health and metabolic homeostasis. [ABSTRACT FROM AUTHOR]

In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body's ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements. [ABSTRACT FROM AUTHOR]

Background: Currently, there is no objective, clinically available tool for the accurate diagnosis of Alzheimer's disease (AD). There is a pressing need for a novel, minimally invasive, cost friendly, and easily accessible tool to diagnose AD, assess disease severity, and prognosticate course. Metabolomics is a promising tool for discovery of new, biologically, and clinically relevant biomarkers for AD detection and classification.Objective: Utilizing artificial intelligence and machine learning, we aim to assess whether a panel of metabolites as detected in plasma can be used as an objective and clinically feasible tool for the diagnosis of mild cognitive impairment (MCI) and AD.Methods: Using a community-based sample cohort acquired from different sites across the US, we adopted an approach combining Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR), Liquid Chromatography coupled with Mass Spectrometry (LC-MS) and various machine learning statistical approaches to identify a biomarker panel capable of identifying those patients with AD and MCI from healthy controls.Results: Of the 212 measured metabolites, 5 were identified as optimal to discriminate between controls, and individuals with MCI or AD. Our models performed with AUC values in the range of 0.72-0.76, with the sensitivity and specificity values ranging from 0.75-0.85 and 0.69-0.81, respectively. Univariate and pathway analysis identified lipid metabolism as the most perturbed biochemical pathway in MCI and AD.Conclusion: A comprehensive method of acquiring metabolomics data, coupled with machine learning techniques, has identified a strong panel of diagnostic biomarkers capable of identifying individuals with MCI and AD. Further, our data confirm what other groups have reported, that lipid metabolism is significantly perturbed in those individuals suffering with dementia. This work may provide additional insight into AD pathogenesis and encourage more in-depth analysis of the AD lipidome. [ABSTRACT FROM AUTHOR]

As do many other immunity-related blood cells, platelets release antimicrobial peptides that kill bacteria, fungi, and even certain viruses. Here we review the literature suggesting that there is a similarity between the antimicrobials released by other blood cells and the amyloid-related Aβ peptide released by platelets. Analyzing the literature, we also propose that platelet-generated Aβ amyloidosis may be more common than currently recognized. This systemic Aβ from a platelet source may participate in various forms of amyloidosis in pathologies ranging from brain cancer, glaucoma, skin Aβ accumulation, and preeclampsia to Alzheimer's disease and late-stage Parkinson's disease. We also discuss the advantages and disadvantages of specific animal models for studying platelet-related Aβ. This field is undergoing rapid change, as it evaluates competing ideas in the light of new experimental observations. We summarized both in order to clarify the role of platelet-generated Aβ peptides in amyloidosis-related health disorders, which may be helpful to researchers interested in this growing area of investigation. [ABSTRACT FROM AUTHOR]

Pre-pregnancy body mass index (BMI) is a major relevance factor, since maternal overweight and obesity can impair the pregnancy outcome and represent risk factors for several neonatal, childhood, and adult conditions, including excessive weight gain, cardiovascular disease, diabetes mellitus, and even behavioral disorders. Currently, breast milk (BM) composition in such category of mothers was not completely defined. In this field, metabolomics represents the ideal technology, able to detect the whole profile of low molecular weight molecules in BM. Limited information is available on human BM metabolites differences in overweight or obese compared to lean mothers. Analyzing all the metabolomics studies published on Medline in English language, this review evaluated the effects that 8 specific types of metabolites found altered by maternal overweight and obesity (nucleotide derivatives, 5-methylthioadenosine, sugar-alcohols, acylcarnitine and amino acids, polyamines, mono-and oligosaccharides, lipids) can exert on the risk of offspring obesity development and other potentially associated health outcomes and complications. However, metabolites variations in samples collected from overweight and obese mothers and the potentially correlated effects highlighted below still need further investigations and should be confirmed in future metabolomics studies on larger samples. Finally, the positive or negative influence of maternal overweight and obesity on the offspring, potentially exerted by breastfeeding, should be analyzed in close correlation with maternal age, genetic and environmental factors, including diet, and taking into account the interactions occurring between BM metabolites and lactobiome. The evaluation of all the factors affecting BM metabolites in overweight and obese mothers can lead to the comprehensive description of such biofluid and the related effects on breastfed subjects, potentially highlighting personalized needs of BM supplementation or short- and long-term prevention strategies to optimize offspring health. [ABSTRACT FROM AUTHOR]

Introduction: The first symptoms of psychosis are frequently shared amongst several neuropsychiatry disorders, which makes the differentiation by clinical diagnosis challenging. Early recognition of symptoms is important in the management of psychosis. Therefore, the implementation of molecular biomarkers will be crucial for transforming the currently used diagnostic and therapeutic approach, improving insights into the underlying biological processes and clinical management. Objectives: To define a set of metabolites that supports diagnosis or prognosis of schizophrenia (SCZ) and bipolar disorder (BD) at first onset psychosis. Methods: Plasma samples from 55 drug-naïve patients, 28 SCZ and 27 BD, and 42 healthy controls (HC). All participants underwent a seminaturalistic treatment regimen, clinically evaluated on a weekly basis until achieving clinical remission. All clinical or sociodemographic aspects considered for this study were equivalent between the groups at first-onset psychosis time point. The plasma samples were analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) using reversed-phase and hydrophilic interaction chromatography. The acquired molecular features were analyzed with MetaboAnalyst. Results: We identified two patient groups with different metabolite profiles. Both groups are composed of SCZ and BD patients. We found differences between these two groups regarding general symptoms of PANSS score after remission (p = 0.008), and the improvement of general symptoms (delta of the score at remission minus the baseline) (−0.50 vs. −0.33, p = 0.019). Conclusion: Our results suggest that plasma metabolite profiles cluster clinical remission phenotypes based on PANSS general psychopathology scores. [ABSTRACT FROM AUTHOR]

The metabolomic profile of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) may suggest potential diagnostic biomarkers and provide information on the pathophysiology of dementia. Our aim was to quantify plasmatic metabolites of AD patients, MCI and controls. We investigated the metabolomic profile—using the AbsoluteIDQ®p180 assay—of 79 older adults with primary cognitive impairment (34 AD and 20 MCI) and 25 healthy elders (controls). A cluster analysis revealed that a combination C12-DC, C12 and PCaaC26:0 could differentiate the patients according to diagnostic. Future studies should combine metabolomic profiles with other biomarkers to identify diagnostic groups. [ABSTRACT FROM AUTHOR]

The clinical diagnosis of Alzheimer's disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process. Abnormalities in amyloid-beta precursor protein (APP) metabolism and in the level of APP secretases have been demonstrated in platelets, and to a lesser extent in leukocytes, of AD patients, with conflicting results. The aim of the present study was to compare the protein level of the APP secretases A-disintegrin and metalloprotease 10 (ADAM10), Beta-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PSEN1) in platelets and leukocytes from 20 non-medicated older adults with AD and 20 healthy elders, and to determine the potential use of these biomarkers to discriminate cases of AD from controls. The protein levels of all APP secretases were significantly higher in platelets compared to leukocytes. We found statistically a significant decrease in ADAM10 (52.5%, p < 0.0001) and PSEN1 (32%, p = 0.02) in platelets from AD patients compared to controls, but not in leukocytes. Combining all three secretases to generate receiver-operating characteristic (ROC) curves, we found a good discriminatory effect (AD vs. controls) when using platelets (the area under the curve—AUC—0.90, sensitivity 88.9%, specificity 66.7%, p = 0.003), but not in leukocytes (AUC 0.65, sensitivity 77.8%, specificity 50.0%, p = 0.2). Our findings indicate that platelets represent a better biological matrix than leukocytes to address the peripheral level of APP secretases. In addition, combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls. [ABSTRACT FROM AUTHOR]