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The Journal of Pharmacology and... May 2024Haloperidol decanoate (HD) was implicated in cognitive impairment. Agomelatine (AGO) was claimed to improve cognition. We aimed at investigating the effects of HD + low-...
High- Dose Agomelatine Combined to Haloperidol Decanoate Improves Cognition, Downregulating , Against Upregulating , Maintaining , Though Alters Cardiac Electrophysiology.
Haloperidol decanoate (HD) was implicated in cognitive impairment. Agomelatine (AGO) was claimed to improve cognition. We aimed at investigating the effects of HD + low- or high- dose AGO on cognition, verifying the melatonergic/dopaminergic-to-the cholinergic hypothesis of cognition and exploring relevant cardiovascular issues in adult male albino rats. HD + high- dose AGO prolonged the step through latency increased the time spent in bright light , reduced the time spent in dim light , and increased the percent of alternations despite the reductions in brain acetylcholine level by -10.67%, Neurodegeneration was minimal, while the mean power frequency of source wave was reduced by -23.39% Concurrently, the relative expression of brain melatonin type-2 receptors was reduced by , against increased expressions of dopamine type- 5 receptors ) and angiopoietin-like 4 ( ). Meanwhile, ECG demonstrated inverted P wave and reduced P wave duration by and PR interval , prolonged RR interval by , increased R wave amplitude by , a depressed ST segment and inverted T wave. In rats administered AGO, HD, or HD+ low- dose AGO, Alzheimer's disease-like neuropathologic features were more evident, accompanied by extensive ECG and neurochemical alterations. HD + high- dose AGO enhances cognition but alters cardiac electrophysiology. Given the issue of cognitive impairment associated with haloperidol decanoate (HD) and the claimed cognitive enhancing activity of agomelatine (AGO), combined high- dose AGO to HD improved cognition of adult male rats, and exhibited minimal neurodegenerative changes. HD+ high- dose AGO was relatively safe regarding triggering epileptogenesis, while altered cardiac electrophysiology. In presence of low ACh, the melatonergic/dopaminergic hypothesis, added to ANGPTL4 and KLF9, could have some clue, thus, offering novel targets for pharmacologic manipulation of cognition.
PubMed: 38816228
DOI: 10.1124/jpet.123.002087 -
Frontiers in Aging Neuroscience 2024Early Alzheimer's disease (AD) diagnosis remains challenging, necessitating specific biomarkers for timely detection. This study aimed to identify such biomarkers and...
OBJECTIVE
Early Alzheimer's disease (AD) diagnosis remains challenging, necessitating specific biomarkers for timely detection. This study aimed to identify such biomarkers and explore their associations with cognitive decline.
METHODS
A cohort of 1759 individuals across cognitive aging stages, including healthy controls (HC), mild cognitive impairment (MCI), and AD, was examined. Utilizing nine biomarkers from structural MRI (sMRI), diffusion tensor imaging (DTI), and positron emission tomography (PET), predictions were made for Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDRSB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS). Biomarkers included four sMRI (e.g., average thickness [ATH]), four DTI (e.g., mean diffusivity [MD]), and one PET Amyloid-β (Aβ) measure. Ensemble regression tree (ERT) technique with bagging and random forest approaches were applied in four groups (HC/MCI, HC/AD, MCI/AD, and HC/MCI/AD).
RESULTS
Aβ emerged as a robust predictor of cognitive scores, particularly in late-stage AD. Volumetric measures, notably ATH, consistently correlated with cognitive scores across early and late disease stages. Additionally, ADAS demonstrated links to various neuroimaging biomarkers in all subject groups, highlighting its efficacy in monitoring brain changes throughout disease progression. ERT identified key brain regions associated with cognitive scores, such as the right transverse temporal region for Aβ, left and right entorhinal cortex, left inferior temporal gyrus, and left middle temporal gyrus for ATH, and the left uncinate fasciculus for MD.
CONCLUSION
This study underscores the importance of an interdisciplinary approach in understanding AD mechanisms, offering potential contributions to early biomarker development.
PubMed: 38813532
DOI: 10.3389/fnagi.2024.1356656 -
Frontiers in Aging Neuroscience 2024Alzheimer's disease (AD) is a common neurodegenerative dementia, characterized by abnormal dynamic functional connectivity (DFC). Traditional DFC analysis, assuming...
BACKGROUND
Alzheimer's disease (AD) is a common neurodegenerative dementia, characterized by abnormal dynamic functional connectivity (DFC). Traditional DFC analysis, assuming linear brain dynamics, may neglect the complexity of the brain's nonlinear interactions. Energy landscape analysis offers a holistic, nonlinear perspective to investigate brain network attractor dynamics, which was applied to resting-state fMRI data for AD in this study.
METHODS
This study utilized resting-state fMRI data from 60 individuals, comparing 30 Alzheimer's patients with 30 controls, from the Alzheimer's Disease Neuroimaging Initiative. Energy landscape analysis was applied to the data to characterize the aberrant brain network dynamics of AD patients.
RESULTS
The AD group stayed in the co-activation state for less time than the healthy control (HC) group, and a positive correlation was identified between the transition frequency of the co-activation state and behavior performance. Furthermore, the AD group showed a higher occurrence frequency and transition frequency of the cognitive control state and sensory integration state than the HC group. The transition between the two states was positively correlated with behavior performance.
CONCLUSION
The results suggest that the co-activation state could be important to cognitive processing and that the AD group possibly raised cognitive ability by increasing the occurrence and transition between the impaired cognitive control and sensory integration states.
PubMed: 38813531
DOI: 10.3389/fnagi.2024.1375091 -
Frontiers in Aging Neuroscience 2024Accurately predicting when patients with mild cognitive impairment (MCI) will progress to dementia is a formidable challenge. This work aims to develop a predictive deep...
OBJECTIVES
Accurately predicting when patients with mild cognitive impairment (MCI) will progress to dementia is a formidable challenge. This work aims to develop a predictive deep learning model to accurately predict future cognitive decline and magnetic resonance imaging (MRI) marker changes over time at the individual level for patients with MCI.
METHODS
We recruited 657 amnestic patients with MCI from the Samsung Medical Center who underwent cognitive tests, brain MRI scans, and amyloid-β (Aβ) positron emission tomography (PET) scans. We devised a novel deep learning architecture by leveraging an attention mechanism in a recurrent neural network. We trained a predictive model by inputting age, gender, education, apolipoprotein E genotype, neuropsychological test scores, and brain MRI and amyloid PET features. Cognitive outcomes and MRI features of an MCI subject were predicted using the proposed network.
RESULTS
The proposed predictive model demonstrated good prediction performance (AUC = 0.814 ± 0.035) in five-fold cross-validation, along with reliable prediction in cognitive decline and MRI markers over time. Faster cognitive decline and brain atrophy in larger regions were forecasted in patients with Aβ (+) than with Aβ (-).
CONCLUSION
The proposed method provides effective and accurate means for predicting the progression of individuals within a specific period. This model could assist clinicians in identifying subjects at a higher risk of rapid cognitive decline by predicting future cognitive decline and MRI marker changes over time for patients with MCI. Future studies should validate and refine the proposed predictive model further to improve clinical decision-making.
PubMed: 38813529
DOI: 10.3389/fnagi.2024.1356745 -
Turkish Journal of Medical Sciences 2023There are reports stating that deteriorations in metal homeostasis in neurodegenerative diseases promote abnormal protein accumulation. In this study, the serum metal...
BACKGROUND/AIM
There are reports stating that deteriorations in metal homeostasis in neurodegenerative diseases promote abnormal protein accumulation. In this study, the serum metal levels in Alzheimer's disease (AD) and Parkinson's disease (PD) and its relationship with the cortical regions of the brain were investigated.
MATERIALS AND METHODS
The patients were divided into 3 groups consisting of the AD group, PD group, and healthy control group (n = 15 for each). The volumes of specific brain regions were measured over the participants' 3dimensional magnetic resonance images, and they were compared across the groups. Copper, zinc, iron, and ferritin levels in the serums were determined, and their correlations with the brain region volumes were examined.
RESULTS
The volumes of left hippocampus and right substantia nigra were lower in the AD and PD groups, while the volume of the left nucleus caudatus (CdN) and bilateral insula were lower in the AD group compared to the control group. Serum zinc levels were lower in the AD and PD groups, while the iron level was lower in the PD group in comparison to the control group. In addition, the serum ferritin level was higher in the AD group than in the control group. Serum zinc and copper levels in the AD group were positively correlated with the volumes of the right entorhinal cortex, thalamus, CdN, and insula. Serum zinc and copper levels in the PD group showed a negative correlation with the left nucleus accumbens (NAc), right putamen, and right insula volumes. While the serum ferritin level in the PD group displayed a positive correlation with the bilateral CdN, putamen, and NAc, as well as the right hippocampus and insula volumes, no area was detected that showed a correlation with the serum ferritin level in the AD group.
CONCLUSION
A relationship was determined between the serum metal levels in the AD and PD groups and certain brain cortical regions that showed volumetric changes, which can be important for the early diagnosis of neurodegenerative diseases.
Topics: Humans; Male; Female; Aged; Alzheimer Disease; Zinc; Iron; Magnetic Resonance Imaging; Parkinson Disease; Middle Aged; Ferritins; Brain; Copper; Neurodegenerative Diseases; Case-Control Studies; Metals
PubMed: 38812995
DOI: 10.55730/1300-0144.5714 -
Frontiers in Neuroscience 2024Pregnancy and the postpartum period induce physiological changes that can influence women's cognitive functions. Alzheimer's disease (AD) has a higher prevalence in...
Pregnancy and the postpartum period induce physiological changes that can influence women's cognitive functions. Alzheimer's disease (AD) has a higher prevalence in women and is exacerbated by early life stress. In the present study, we found that late adolescent social isolation combined with the experience of pregnancy and delivery accelerates the onset of cognitive deficits in 5xFAD dams, particularly affecting their ability to recognize novelty. These cognitive deficits manifested as early as 16 weeks, earlier than the usual timeline for these mice, and were closely associated with increased levels of corticosterone, suggesting dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Notably, the presence of -amyloid plaques in brain regions associated with novelty recognition did not significantly contribute to these deficits. This highlights the potential role of stress and HPA axis dysregulation in the development of cognitive impairments related to AD, and underscores the need for further investigation.
PubMed: 38812977
DOI: 10.3389/fnins.2024.1366199 -
Frontiers in Nutrition 2024This study focuses on the assessment of extra virgin olive-oil and olive fruit-based formulations enriched with natural antioxidants as potential nutritional supplements...
INTRODUCTION
This study focuses on the assessment of extra virgin olive-oil and olive fruit-based formulations enriched with natural antioxidants as potential nutritional supplements for alleviating symptoms and long-term consequences of illnesses whose molecular pathophysiology is affected by oxidative stress and inflammation, such as Alzheimer's disease (AD).
METHODS
Besides evaluating cell viability and proliferation capacity of human hepatocellular carcinoma HepG2 cells exposed to formulations in culture, hepatotoxicity was also considered as an additional safety measure using quantitative real-time PCR on RNA samples isolated from the cell cultures and applying approaches of targeted molecular analysis to uncover potential pathway effects through gene expression profiling. Furthermore, the formulations investigated in this work contrast the addition of natural extract with chemical forms and evaluate the antioxidant delivery mode on cell toxicity.
RESULTS
The results indicate minimal cellular toxicity and a significant beneficial impact on metabolic molecular pathways in HepG2 cell cultures, thus paving the way for innovative therapeutic strategies using olive-oil and antioxidants in dietary supplements to minimize the long-term effects of oxidative stress and inflammatory signals in individuals being suffered by disorders like AD.
DISCUSSION
Overall, the experimental design and the data obtained support the notion of applying innovative molecular methodologies and research techniques to evidently advance the delivery, as well as the scientific impact and validation of nutritional supplements and dietary products to improve public health and healthcare outcomes.
PubMed: 38812942
DOI: 10.3389/fnut.2024.1388492 -
Practical Laboratory Medicine May 2024Insulin degrading enzyme (IDE) plays a critical role in degrading insulin and beta-forming proteins, implicating its significance as a biomarker in metabolic dysfunction...
Insulin degrading enzyme (IDE) plays a critical role in degrading insulin and beta-forming proteins, implicating its significance as a biomarker in metabolic dysfunction and neurocognitive disorders, including Alzheimer's disease (AD). Understanding the impact of pre-analytic conditions of in vitro IDE levels is imperative for reliable biomarker assessment. This study explored the influence of freeze-thaw cycles, storage temperature, and storage time on IDE levels in human serum. Serum samples from seven healthy volunteers were subjected to various storage conditions, including refrigeration (4 °C) and freezing (-20 °C and -80 °C) for 24 h and six months, with differing freeze-thaw cycles. In vitro IDE levels were measured at 24 h and after 6 months using ELISA. Results indicate that while short-term storage at either -20 °C or -80 °C yielded similar IDE levels, prolonged storage and multiple freeze-thaw cycles significantly impacted IDE stability, with colder temperatures exhibiting better preservation. Although further research with larger cohorts and longer storage time is warranted to establish clinical significance, our study suggests preferential use of unthawed samples or consistent freeze-thaw conditions for accurate IDE assessment. Thus, optimizing sample storage conditions is paramount for reliable IDE biomarker analysis in clinical and research settings.
PubMed: 38812908
DOI: 10.1016/j.plabm.2024.e00400 -
Frontiers in Cellular Neuroscience 2024This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia,... (Review)
Review
This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.
PubMed: 38812793
DOI: 10.3389/fncel.2024.1391537 -
Alcohol Research : Current Reviews 2024By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a... (Review)
Review
PURPOSE
By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a risk factor for dementia: every 5 years beyond age 65, the risk doubles; approximately one-third of those older than age 85 are diagnosed with dementia. As current alcohol consumption among older adults is significantly higher compared to previous generations, a pressing question is whether drinking alcohol increases the risk for Alzheimer's disease or other forms of dementia.
SEARCH METHODS
Databases explored included PubMed, Web of Science, and ScienceDirect. To accomplish this narrative review on the effects of alcohol consumption on dementia risk, the literature covered included clinical diagnoses, epidemiology, neuropsychology, postmortem pathology, neuroimaging and other biomarkers, and translational studies. Searches conducted between January 12 and August 1, 2023, included the following terms and combinations: "aging," "alcoholism," "alcohol use disorder (AUD)," "brain," "CNS," "dementia," "Wernicke," "Korsakoff," "Alzheimer," "vascular," "frontotemporal," "Lewy body," "clinical," "diagnosis," "epidemiology," "pathology," "autopsy," "postmortem," "histology," "cognitive," "motor," "neuropsychological," "magnetic resonance," "imaging," "PET," "ligand," "degeneration," "atrophy," "translational," "rodent," "rat," "mouse," "model," "amyloid," "neurofibrillary tangles," "α-synuclein," or "presenilin." When relevant, "species" (i.e., "humans" or "other animals") was selected as an additional filter. Review articles were avoided when possible.
SEARCH RESULTS
The two terms "alcoholism" and "aging" retrieved about 1,350 papers; adding phrases-for example, "postmortem" or "magnetic resonance"-limited the number to fewer than 100 papers. Using the traditional term, "alcoholism" with "dementia" resulted in 876 citations, but using the currently accepted term "alcohol use disorder (AUD)" with "dementia" produced only 87 papers. Similarly, whereas the terms "Alzheimer's" and "alcoholism" yielded 318 results, "Alzheimer's" and "alcohol use disorder (AUD)" returned only 40 citations. As pertinent postmortem pathology papers were published in the 1950s and recent animal models of Alzheimer's disease were created in the early 2000s, articles referenced span the years 1957 to 2024. In total, more than 5,000 articles were considered; about 400 are herein referenced.
DISCUSSION AND CONCLUSIONS
Chronic alcohol misuse accelerates brain aging and contributes to cognitive impairments, including those in the mnemonic domain. The consensus among studies from multiple disciplines, however, is that alcohol misuse can increase the risk for dementia, but not necessarily Alzheimer's disease. Key issues to consider include the reversibility of brain damage following abstinence from chronic alcohol misuse compared to the degenerative and progressive course of Alzheimer's disease, and the characteristic presence of protein inclusions in the brains of people with Alzheimer's disease, which are absent in the brains of those with AUD.
Topics: Humans; Dementia; Alcoholism; Aged; Animals; Aged, 80 and over; Alcohol Drinking; Brain; Alzheimer Disease; Risk Factors
PubMed: 38812709
DOI: 10.35946/arcr.v44.1.03