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Daily Energy Intake Distribution and Cognitive Performance in Non-Demented Individuals.

Cognitive disorders have become important public health issues around the world. Studies evaluating the association between cognitive decline and food timing are lacking. The objective of this study was to examine the potential association between energy intake distribution during the day and cognitive performance in cognitively healthy and mildly cognitive impaired individuals. Data were derived from the ongoing Albion study which includes people aged 40 years or older who have a positive family history of cognitive disorder or concern about their cognitive status. A thorough dietary and cognitive assessment was performed. Participants consuming low energy intake at the beginning of the day or high energy at the end of the day had higher cognitive function compared to participants characterized by the opposite pattern. This trend remained statistically significant even after adjustment for potential confounders (

Dietary Responses of Dementia-Related Genes Encoding Metabolic Enzymes.

The age-related loss of the cognitive function is a growing concern for global populations. Many factors that determine cognitive resilience or dementia also have metabolic functions. However, this duality is not universally appreciated when the action of that factor occurs in tissues external to the brain. Thus, we examined a set of genes involved in dementia, i.e., those related to vascular dementia, Alzheimers disease, Parkinsons disease, and the human metabolism for activity in 12 metabolically active tissues. Mining the Genotype-Tissue Expression (GTEx) data showed that most of these metabolism-dementia (MD) genes (62 of 93, 67%) exhibit a higher median expression in any of the metabolically active tissues than in the brain. After identifying that several MD genes served as blood-based biomarkers of longevity in other studies, we examined the impact of the intake of food, nutrients, and other dietary factors on the expression of MD genes in whole blood in the Framingham Offspring Study (

miRNAs and Alzheimers Disease Exploring the Role of Inflammation and Vitamin E in an Old-Age Population.

Alzheimers disease (AD) is the most frequent cause of dementia worldwide and represents one of the leading factors for severe disability in older persons. Although its etiology is not fully known yet, AD may develop due to multiple factors, including inflammation and oxidative stress, conditions where microRNAs (miRNAs) seem to play a pivotal role as a molecular switch. All these aspects may be modulated by nutritional factors. Among them, vitamin E has been widely studied in AD, given the plausibility of its various biological functions in influencing neurodegeneration. From a cohort of old-aged people, we measured eight vitamin E forms (tocopherols and tocotrienols), thirty cytokineschemokines, and thirteen exosome-extracted miRNAs in plasma of subjects suffering from subjects affected by AD and age-matched healthy controls (HC). The sample population included 80 subjects (40 AD and 40 HC) with a mean age of 77.6 ± 3.8 years, mostly women (45 56.2%). Of the vitamin E forms, only α-tocopherol differed between groups, with significantly lower levels in AD. Regarding the examined inflammatory molecules, G-CSF, GM-CSF, INF-α2, IL-3, and IL-8 were significantly higher and IL-17 lower in AD than HC. Among all miRNAs examined, AD showed downregulation of miR-9, miR-21, miR29-b, miR-122, and miR-132 compared to controls. MiR-122 positively and significantly correlated with some inflammatory molecules (GM-CSF, INF-α2, IL-1α, IL-8, and MIP-1β) as well as with α-tocopherol even after correction for age and gender. A final binary logistic regression analysis showed that α-tocopherol serum levels were associated with a higher AD probability and partially mediated by miR-122. Our results suggest an interplay between α-tocopherol, inflammatory molecules, and microRNAs in AD, where miR-122 may be a good candidate as modulating factor.

Anti-Neuroinflammatory Potential of Natural Products in the Treatment of Alzheimers Disease.

Alzheimers disease (AD) is an age-related chronic progressive neurodegenerative disease, which is the main cause of dementia in the elderly. Much evidence shows that the onset and late symptoms of AD are caused by multiple factors. Among them, aging is the main factor in the pathogenesis of AD, and the most important risk factor for AD is neuroinflammation. So far, there is no cure for AD, but the relationship between neuroinflammation and AD may provide a new strategy for the treatment of AD. We herein discussed the main etiology hypothesis of AD and the role of neuroinflammation in AD, as well as anti-inflammatory natural products with the potential to prevent and alleviate AD symptoms, including alkaloids, steroids, terpenoids, flavonoids and polyphenols, which are available with great potential for the development of anti-AD drugs.

Rational Design of Nitrogen-Doped Carbon Dots for Inhibiting

The fibrillization and abnormal aggregation of

In Silico Drug Design and Analysis of Dual Amyloid-Beta and Tau Protein-Aggregation Inhibitors for Alzheimers Disease Treatment.

Alzheimers disease (AD) is a progressive and irreversible neurodegenerative disorder that gradually leads to the state of dementia. The main features of AD include the deposition of amyloid-beta peptides (Aβ), forming senile plaques, and the development of neurofibrillary tangles due to the accumulation of hyperphosphorylated Tau protein (p-tau) within the brain cells. In this report, seven dual-inhibitor molecules (L

Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders.

Neurological diseases including Alzheimers, Huntingtons disease, Parkinsons disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABA

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs.

Central nervous system (CNS) disorders are a therapeutic area in drug discovery where demand for new treatments greatly exceeds approved treatment options. This is complicated by the high failure rate in late-stage clinical trials, resulting in exorbitant costs associated with bringing new CNS drugs to market. Computer-aided drug design (CADD) techniques minimise the time and cost burdens associated with drug research and development by ensuring an advantageous starting point for pre-clinical and clinical assessments. The key elements of CADD are divided into ligand-based and structure-based methods. Ligand-based methods encompass techniques including pharmacophore modelling and quantitative structure activity relationships (QSARs), which use the relationship between biological activity and chemical structure to ascertain suitable lead molecules. In contrast, structure-based methods use information about the binding site architecture from an established protein structure to select suitable molecules for further investigation. In recent years, deep learning techniques have been applied in drug design and present an exciting addition to CADD workflows. Despite the difficulties associated with CNS drug discovery, advances towards new pharmaceutical treatments continue to be made, and CADD has supported these findings. This review explores various CADD techniques and discusses applications in CNS drug discovery from 2018 to November 2022.

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Role of Nanomedicine-Based Therapeutics in the Treatment of CNS Disorders.

Central nervous system disorders, especially neurodegenerative diseases, are a public health priority and demand a strong scientific response. Various therapy procedures have been used in the past, but their therapeutic value has been insufficient. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier is two of the barriers that protect the central nervous system (CNS), but are the main barriers to medicine delivery into the CNS for treating CNS disorders, such as brain tumors, Parkinsons disease, Alzheimers disease, and Huntingtons disease. Nanotechnology-based medicinal approaches deliver valuable cargos targeting molecular and cellular processes with greater safety, efficacy, and specificity than traditional approaches. CNS diseases include a wide range of brain ailments connected to short- and long-term disability. They affect millions of people worldwide and are anticipated to become more common in the coming years. Nanotechnology-based brain therapy could solve the BBB problem. This review analyzes nanomedicines role in medication delivery immunotherapy, chemotherapy, and gene therapy are combined with nanomedicines to treat CNS disorders. We also evaluated nanotechnology-based approaches for CNS disease amelioration, with the intention of stimulating the immune system by delivering medications across the BBB.

Comparison of Oleocanthal-Low EVOO and Oleocanthal against Amyloid-β and Related Pathology in a Mouse Model of Alzheimers Disease.

Alzheimers disease (AD) is characterized by several pathological hallmarks, including the deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, and neuroinflammation. Growing evidence support the neuroprotective effects of extra-virgin olive oil (EVOO) and oleocanthal (OC). In this work, we aimed to evaluate and compare the beneficial effects of equivalent doses of OC-low EVOO (0.5 mg total phenolic contentkg) and OC (0.5 mg OCkg) on Aβ and related pathology and to assess their effect on neuroinflammation in a 5xFAD mouse model with advanced pathology. Homozygous 5xFAD mice were fed with refined olive oil (ROO), OC-low EVOO, or OC for 3 months starting at the age of 3 months. Our findings demonstrated that a low dose of 0.5 mgkg EVOO-phenols and OC reduced brain Aβ levels and neuroinflammation by suppressing the nuclear factor-κB (NF-κB) pathway and reducing the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. On the other hand, only OC suppressed the receptor for advanced glycation endproductshigh-mobility group box 1 (RAGEHMGB1) pathway. In conclusion, our results indicated that while OC-low EVOO demonstrated a beneficial effect against Aβ-related pathology in 5xFAD mice, EVOO rich with OC could provide a higher anti-inflammatory effect by targeting multiple mechanisms. Collectively, diet supplementation with EVOO or OC could prevent, halt progression, and treat AD.

Alkaloid Profile in Wild Autumn-Flowering Daffodils and Their Acetylcholinesterase Inhibitory Activity.

Amaryllidaceae alkaloids are secondary metabolites with interesting medicinal properties. Almost every

Efficient Combination of Complex Chromatography, Molecular Docking and Enzyme Kinetics for Exploration of Acetylcholinesterase Inhibitors from

Neuroprotective Effect of α-Lipoic Acid against Aβ

The prevalence of Alzheimers disease (AD) is significantly increasing due to the aging world population, and the currently available drug treatments cannot cure or even slow its progression. α-lipoic acid (LA) is a biological factor widely found in spinach and meat and can dissolve in both lipid and aqueous phases. In medicine, LA has been shown to reduce the symptoms of diabetic polyneuropathy, acute kidney injury, cancers, and some metabolism-related diseases. This study to proves that α-lipoic acid (LA) can stabilize the cognitive function of patients with Alzheimers disease (AD). BV2 cells were divided into control, LA, Aβ

New Triazine Derivatives as Serotonin 5-HT

Since the number of people with Alzheimers disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT

A Review on Recent Approaches on Molecular Docking Studies of Novel Compounds Targeting Acetylcholinesterase in Alzheimer Disease.

Alzheimers disease (AD), a neurodegenerative brain disorder that affects millions of people worldwide, is characterized by memory loss and cognitive decline. Low levels of acetylcholine and abnormal levels of beta-amyloid, T protein aggregation, inflammation, and oxidative stress, have been associated with AD, and therefore, research has been oriented towards the cholinergic system and primarily on acetylcholinesterase (AChE) inhibitors. In this review, we are focusing on the discovery of AChE inhibitors using computer-based modeling and simulation techniques, covering the recent literature from 2018-2022. More specifically, the review discusses the structures of novel, potent acetylcholinesterase inhibitors and their binding mode to AChE, as well as the physicochemical requirements for the design of potential AChE inhibitors.

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors A Molecular Modeling Design Approach.

Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimers disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the

Anti-Amyloidogenic Effects of

Alzheimers disease (AD) is a serious neurodegenerative brain disease that interferes with daily life. The accumulation of beta-amyloid (Aβ), along with oxidative stress-inducing neurocellular apoptosis, has been considered one of the causes of AD. Thus, the purpose of this study is to find natural products that can reduce Aβ accumulation. The ethanol extract of

Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions.

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGPIGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGPIGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGPIGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGPIGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for-and an intervention to improve-IGF-1 function.

Could Temperamental Features Modulate Participation in Clinical Trials

The prodromal stages of Alzheimers disease (AD) are the primary focus of research aimed at slowing disease progression. This study explores the influence of affective temperament on the motivation of people with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) to participate in clinical trials. One hundred four subjects with MCI and SCD were screened for participation in pharmacological and non-pharmacological trials. Affective temperament was assessed based on the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego (TEMPS) scale. Demographic variables and temperament subscales scores were compared between MCI and SCD patients and among patients participating in the pharmacological trial, the non-pharmacological trial and refusing participation. Twenty-one subjects consented to participate in the pharmacological trial, seventy consented to the non-pharmacological trial and thirteen refused to participate in any trial. Patients with SCD had greater education and more depressive temperamental traits than those with MCI. While older age, higher education and anxious temperament were negatively associated with participation in the pharmacological trial, irritable temperamental positively predicted pharmacological trial participation. In conclusion, temperamental features may affect the willingness of patients with MCI and SCD to take part in clinical trials and, especially, the choice to participate in pharmacological studies.

Increased Hippocampal-Inferior Temporal Gyrus White Matter Connectivity following Donepezil Treatment in Patients with Early Alzheimers Disease A Diffusion Tensor Probabilistic Tractography Study.

The incidence of Alzheimers disease (AD) has been increasing each year, and a defective hippocampus has been primarily associated with an early stage of AD. However, the effect of donepezil treatment on hippocampus-related networks is unknown. Thus, in the current study, we evaluated the hippocampal white matter (WM) connectivity in patients with early-stage AD before and after donepezil treatment using probabilistic tractography, and we further determined the WM integrity and changes in brain volume. Ten patients with early-stage AD (mean age 72.4 ± 7.9 years seven females and three males) and nine healthy controls (HC mean age 70.7 ± 3.5 years six females and three males) underwent a magnetic resonance (MR) examination. After performing the first MR examination, the patients received donepezil treatment for 6 months. The brain volumes and diffusion tensor imaging scalars of 11 regions of interest (the superiormiddleinferior frontal gyrus, the superiormiddleinferior temporal gyrus, the amygdala, the caudate nucleus, the hippocampus, the putamen, and the thalamus) were measured using MR imaging and DTI, respectively. Seed-based structural connectivity analyses were focused on the hippocampus. The patients with early AD had a lower hippocampal volume and WM connectivity with the superior frontal gyrus and higher mean diffusivity (MD) and radial diffusivity (RD) in the amygdala than HC (

Oxidative Stress and Aging as Risk Factors for Alzheimers Disease and Parkinsons Disease The Role of the Antioxidant Melatonin.

Aging and neurodegenerative diseases share common hallmarks, including mitochondrial dysfunction and protein aggregation. Moreover, one of the major issues of the demographic crisis today is related to the progressive rise in costs for care and maintenance of the standard living condition of aged patients with neurodegenerative diseases. There is a divergence in the etiology of neurodegenerative diseases. Still, a disturbed endogenous pro-oxidantsantioxidants balance is considered the crucial detrimental factor that makes the brain vulnerable to aging and progressive neurodegeneration. The present review focuses on the complex relationships between oxidative stress, autophagy, and the two of the most frequent neurodegenerative diseases associated with aging, Alzheimers disease (AD) and Parkinsons disease (PD). Most of the available data support the hypothesis that a disturbed antioxidant defense system is a prerequisite for developing pathogenesis and clinical symptoms of ADs and PD. Furthermore, the release of the endogenous hormone melatonin from the pineal gland progressively diminishes with aging, and peoples susceptibility to these diseases increases with age. Elucidation of the underlying mechanisms involved in deleterious conditions predisposing to neurodegeneration in aging, including the diminished role of melatonin, is important for elaborating precise treatment strategies for the pathogenesis of AD and PD.

PDIA3 Expression Is Altered in the Limbic Brain Regions of Triple-Transgenic Mouse Model of Alzheimers Disease.

In the present study, we used a mouse model of Alzheimers disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aβ and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- andor pathology-dependent, corroborating the ER chaperones involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD.

Prevalence and Mechanisms of Skeletal Muscle Atrophy in Metabolic Conditions.

Skeletal muscle atrophy is prevalent in a myriad of pathological conditions, such as diabetes, denervation, long-term immobility, malnutrition, sarcopenia, obesity, Alzheimers disease, and cachexia. This is a critically important topic that has significance in the health of the current society, particularly older adults. The most damaging effect of muscle atrophy is the decreased quality of life from functional disability, increased risk of fractures, decreased basal metabolic rate, and reduced bone mineral density. Most skeletal muscle in humans contains slow oxidative, fast oxidative, and fast glycolytic muscle fiber types. Depending on the pathological condition, either oxidative or glycolytic muscle type may be affected to a greater extent. This review article discusses the prevalence of skeletal muscle atrophy and several mechanisms, with an emphasis on high-fat, high-sugar diet patterns, obesity, and diabetes, but including other conditions such as sarcopenia, Alzheimers disease, cancer cachexia, and heart failure.

Gemfibrozil-Induced Intracellular Triglyceride Increase in SH-SY5Y, HEK and Calu-3 Cells.

Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood. As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism. However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many diseases, such as Alzheimers disease, cancer, fatty liver disease and type-2 diabetes, treatment with gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase in intracellular triglycerides (SH-SY5Y 170.3% HEK 272.1% Calu-3 448.1%), suggesting that the decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which could be important in diseases, such as Alzheimers disease.

Lipoprotein Metabolism, Protein Aggregation, and Alzheimers Disease A Literature Review.

Alzheimers disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD.

Endothelial Dysfunction in Neurodegenerative Diseases.

The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimers disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.

Alzheimers Precision Neurology Epigenetics of Cytochrome P450 Genes in Circulating Cell-Free DNA for Disease Prediction and Mechanism.

Precision neurology combines high-throughput technologies and statistical modeling to identify novel disease pathways and predictive biomarkers in Alzheimers disease (AD). Brain cytochrome P450 (CYP) genes are major regulators of cholesterol, sex hormone, and xenobiotic metabolism, and they could play important roles in neurodegenerative disorders. Increasing evidence suggests that epigenetic factors contribute to AD development. We evaluated cytosine (CpG)-based DNA methylation changes in AD using circulating cell-free DNA (cfDNA), to which neuronal cells are known to contribute. We investigated CYP-based mechanisms for AD pathogenesis and epigenetic biomarkers for disease detection. We performed a case-control study using 25 patients with AD and 23 cognitively healthy controls using the cfDNA of CYP genes. We performed a logistic regression analysis using the MetaboAnalyst software computer program and a molecular pathway analysis based on epigenetically altered CYP genes using the Cytoscape program. We identified 130 significantly (false discovery rate correction q-value < 0.05) differentially methylated CpG sites within the CYP genes. The top two differentially methylated genes identified were

Deletion of UCP1 in Tg2576 Mice Increases Body Temperature and Exacerbates Alzheimers Disease-Related Pathologies.

We previously demonstrated that the Alzheimers disease (AD)-like model mice, Tg2576, housed at a high ambient temperature of 30 °C for 13 months, exhibited increased body temperature, which increased amyloid-β (Aβ) levels and tau stability, leading to tau phosphorylation and ultimately inducing memory impairment. Here, we aimed to exclude the possible effect of environmental factors associated with the difference in ambient temperature (23 °C vs. 30 °C) and to further clarify the effects of elevated body temperature on AD-like pathologies. We generated uncoupling protein 1 (UCP1) deletion in Tg2576 mice, Tg2576UCP1

Natural Inhibitors of Cholinesterases Chemistry, Structure-Activity and Methods of Their Analysis.

This article aims to provide an updated description and comparison of the data currently available in the literature (from the last 15 years) on the studied natural inhibitors of cholinesterases (IChEs), namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These data also apply to the likely impact of the structures of the compounds on the therapeutic effects of available and potential cholinesterase inhibitors. IChEs are hitherto known compounds with various structures, activities and origins. Additionally, multiple different methods of analysis are used to determine the cholinesterase inhibitor potency. This summary indicates that natural sources are still suitable for the discovery of new compounds with prominent pharmacological activity. It also emphasizes that further studies are needed regarding the mechanisms of action or the structure-activity correlation to discuss the issue of cholinesterase inhibitors and their medical application.

Novel Organoruthenium(II) Complex C1 Selectively Inhibits Butyrylcholinesterase without Side Effects on Neuromuscular Transmission.

Enzyme butyrylcholinesterase (BChE) shows increased activity in some brain regions after progression of Alzheimers disease and is therefore one of the therapeutic targets for symptomatic treatment of this neurodegenerative disorder. The organoruthenium(II) complex (η

Beta-Amyloid Peptide in Tears An Early Diagnostic Marker of Alzheimers Disease Correlated with Choroidal Thickness.

We aimed to evaluate the diagnostic role of Alzheimers disease (AD) biomarkers in tears as well as their association with retinal and choroidal microstructures. In a cross-sectional study, 35 subjects (age 71.7 ± 6.9 years) were included 11 with prodromal AD (MCI), 10 with mild-to-moderate AD, and 14 healthy controls. The diagnosis of AD and MCI was confirmed according to a complete neuropsychological evaluation and PET or MRI imaging. After tear sample collection, β-amyloid peptide Aβ1-42 concentration was analyzed using ELISA, whereas C-terminal fragments of the amyloid precursor protein (APP-CTF) and phosphorylated tau (p-tau) were assessed by Western blot. Retinal layers and choroidal thickness (CT) were acquired by spectral-domain optical coherence tomography (SD-OCT). Aβ1-42 levels in tears were able to detect both MCI and AD patients with a specificity of 93% and a sensitivity of 81% (AUC 0.91). Tear levels of Aβ1-42 were lower, both in the MCI (

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity.

Galantamine is a natural alkaloid extracted from the

Raman Spectroscopy as a Tool to Study the Pathophysiology of Brain Diseases.

The Raman phenomenon is based on the spontaneous inelastic scattering of light, which depends on the molecular characteristics of the dispersant. Therefore, Raman spectroscopy and imaging allow us to obtain direct information, in a label-free manner, from the chemical composition of the sample. Since it is well established that the development of many brain diseases is associated with biochemical alterations of the affected tissue, Raman spectroscopy and imaging have emerged as promising tools for the diagnosis of ailments. A combination of Raman spectroscopy andor imaging with tagged molecules could also help in drug delivery and tracing for treatment of brain diseases. In this review, we first describe the basics of the Raman phenomenon and spectroscopy. Then, we delve into the Raman spectroscopy and imaging modes and the Raman-compatible tags. Finally, we center on the application of Raman in the study, diagnosis, and treatment of brain diseases, by focusing on traumatic brain injury and ischemia, neurodegenerative disorders, and brain cancer.

Melatonin Can Modulate Neurodegenerative Diseases by Regulating Endoplasmic Reticulum Stress.

As people age, their risks of developing degenerative diseases such as cancer, diabetes, Parkinsons Disease (PD), Alzheimers Disease (AD), rheumatoid arthritis, and osteoporosis are generally increasing. Millions of people worldwide suffer from these diseases as they age. In most countries, neurodegenerative diseases are generally recognized as the number one cause afflicting the elderly. Endoplasmic reticulum (ER) stress has been suggested to be associated with some human neurological diseases, such as PD and AD. Melatonin, a neuroendocrine hormone mainly synthesized in the pineal gland, is involved in pleiotropically biological functions, including the control of the circadian rhythm, immune enhancement, and antioxidant, anti-aging, and anti-tumor effects. Although there are many papers on the prevention or suppression of diseases by melatonin, there are very few papers about the effects of melatonin on ER stress in neurons and neurodegenerative diseases. This paper aims to summarize and present the effects of melatonin reported so far, focusing on its effects on neurons and neurodegenerative diseases related to ER stress. Studies have shown that the primary target molecule of ER stress for melatonin is CHOP, and PERK and GRP78BiP are the secondary target molecules. Therefore, melatonin is crucial in protecting neurons and treating neurodegeneration against ER stress.

Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimers Disease.

A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives IC

Molecular Mechanisms Underlying Neuroinflammation Elicited by Occupational Injuries and Toxicants.

Occupational injuries and toxicant exposures lead to the development of neuroinflammation by activating distinct mechanistic signaling cascades that ultimately culminate in the disruption of neuronal function leading to neurological and neurodegenerative disorders. The entry of toxicants into the brain causes the subsequent activation of glial cells, a response known as reactive gliosis. Reactive glial cells secrete a wide variety of signaling molecules in response to neuronal perturbations and thus play a crucial role in the progression and regulation of central nervous system (CNS) injury. In parallel, the roles of protein phosphorylation and cell signaling in eliciting neuroinflammation are evolving. However, there is limited understanding of the molecular underpinnings associated with toxicant- or occupational injury-mediated neuroinflammation, gliosis, and neurological outcomes. The activation of signaling molecules has biological significance, including the promotion or inhibition of disease mechanisms. Nevertheless, the regulatory mechanisms of synergism or antagonism among intracellular signaling pathways remain elusive. This review highlights the research focusing on the direct interaction between the immune system and the toxicant- or occupational injury-induced gliosis. Specifically, the role of occupational injuries, e.g., trips, slips, and falls resulting in traumatic brain injury, and occupational toxicants, e.g., volatile organic compounds, metals, and nanoparticlesnanomaterials in the development of neuroinflammation and neurological or neurodegenerative diseases are highlighted. Further, this review recapitulates the recent advancement related to the characterization of the molecular mechanisms comprising protein phosphorylation and cell signaling, culminating in neuroinflammation.

Correlations between the NMR Lipoprotein Profile,

Cholesterol efflux capacity (CEC) is of interest given its potential relationship with several important clinical conditions including Alzheimers disease. The inactivation of the

Stabilization of Monomeric Tau Protein by All D-Enantiomeric Peptide Ligands as Therapeutic Strategy for Alzheimers Disease and Other Tauopathies.

Alzheimers disease and other tauopathies are the worlds leading causes of dementia and memory loss. These diseases are thought to be caused by the misfolding and aggregation of the intracellular tau protein, ultimately leading to neurodegeneration. The tau protein is involved in a multitude of different neurodegenerative diseases. During the onset of tauopathies, tau undergoes structural changes and posttranslational modifications and aggregates into amyloid fibrils that are able to spread with a prion-like behavior. Up to now, there is no therapeutic agent which effectively controls or reverses the disease. Most of the therapeutics that were developed and underwent clinical trials targeted misfolded or aggregated forms of tau. In the current manuscript, we present the selection and characterization of two all D-enantiomeric peptides that bind monomeric tau protein with a low nanomolar K

A Combination of Caffeine Supplementation and Enriched Environment in an Alzheimers Disease Mouse Model.

A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimers disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD. Here, we investigated whether these effects were synergistic. To that end, previous findings on individual treatments were complemented with unpublished, additional data and analyzed in depth by ANOVA followed by Bonferroni multiple comparison post tests. We further evaluated whether plasma neurofilament light chain levels reflect neuropathological and behavioral changes observed in the experimental groups. While a treatment combining physical activity and caffeine supplementation significantly improved learning and memory function compared to standard-housed vehicle-treated Tg4-42 in tasks such as the Morris water maze, no major additive effect outperforming the effects of the single interventions was observed.

Neurons, Nose, and Neurodegenerative Diseases Olfactory Function and Cognitive Impairment.

Olfactory capacity declines with aging, but increasing evidence shows that smell dysfunction is one of the early signs of prodromal neurodegenerative diseases such as Alzheimers and Parkinsons disease. The study of olfactory ability and its role in neurodegenerative diseases arouses much interest in the scientific community. In neurology, olfactory impairment is a potential early marker for the onset of neurodegenerative diseases, but the underlying mechanism is poorly understood. The loss of smell is considered a clinical sign of early-stage disease and a marker of the diseases progression and cognitive impairment. Highlighting the importance of biological bases of smell and molecular pathways could be fundamental to improve neuroprotective and therapeutic strategies. We focused on the review articles and meta-analyses on olfactory and cognitive impairment. We depicted the neurobiology of olfaction and the most common olfactory tests in neurodegenerative diseases. In addition, we underlined the close relationship between the olfactory and cognitive deficit due to nasal neuroepithelium, which is a direct extension of the CNS in communication with the external environment. Neurons, Nose, and Neurodegenerative diseases highlights the role of olfactory dysfunction as a clinical marker for early stages of neurodegenerative diseases when it is associated with molecular, clinical, and neuropathological correlations.

Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimers Disease.

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimers disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by γ-secretase and influence levels of generated Aβ40 and Aβ42 peptides. The predominant idea in the field is the amyloid hypothesis that states that the resulting increase in Aβ42Aβ40 ratio leads to toxic gain of function due to the accumulation of toxic Aβ42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that loss of function of γ-secretase plays an important role in AD pathogenesis. In the present paper, we propose a mechanistic hypothesis that may potentially reconcile these divergent ideas and observations. We propose that the presence of soluble Aβ peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Aβ peptides, we concluded that Aβ42 peptides and Aβ40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Aβ in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Aβ produced and in the Aβ40Aβ42 ratio, suggesting that the concentration of soluble Aβ in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Aβ production may also occur as a result of age-related accumulation of cholesterol and lipid oxidation products in postsynaptic spines. Our analysis more easily reconciled with the loss of γ-secretase function hypothesis than with the toxic gain of Aβ42 function idea. These results may also explain why inhibitors of β- and γ- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Aβ levels in the endosomal compartments.

Oleracone F Alleviates Cognitive Impairment and Neuropathology in APPswePSEN1dE9 Mice by Reducing the Expression of Vascular Cell Adhesion Molecule and Leukocyte Adhesion to Brain Vascular Endothelial Cells.

Alzheimers disease (AD) is the most common neurodegenerative disease and the blood-brain barrier dysfunction has been suggested as a key pathological feature of the disease. Our research group successfully established a synthetic protocol for oleracones, a novel series of flavonoids isolated from the plant extract of

Insights from a Bibliometrics-Based Analysis of Publishing and Research Trends on Cerium Oxide from 1990 to 2020.

The purpose of this study is to evaluate the literature for research trends on cerium oxide from 1990 to 2020 and identify gaps in knowledge in the emerging application(s) of CeONP. Bibliometric methods were used to identify themes in database searches from PubMed, Scopus and Web of Science Core Collection using SWIFT-Review, VOSviewer and SciMAT software programs. A systematic review was completed on published cerium oxide literature extracted from the Scopus database (

Molecular Mechanisms of Neuroinflammation in Aging and Alzheimers Disease Progression.

Aging is the most prominent risk factor for late-onset Alzheimers disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimers disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimers disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.

The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimers Disease.

Pathogenic changes in γ-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of γ-secretase with its substrate. We analyze the saturation of γ-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of γ-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic Aβ proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-βCTF-APP substrate and its different Aβ products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-βCTF-APP substrate and β-secretase path can be more toxic than the C83-αCTF-APP substrate and α-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-βCTF-APP substrate to γ-secretase can be controlled by substrate channeling between the nicastrin and β-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in γ-secretase activity and Aβ metabolism in different sporadic and familial cases of Alzheimers disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between γ-secretase activity and amyloid metabolism.

An Intervention on Anxiety Symptoms in Moderate Alzheimers Disease through Virtual Reality A Feasibility Study and Lessons Learned.

(1) Background Although cognitive impairment is considered the core deficit of dementia, anxiety disorders also have a negative influence on the social and daily life of the affected population. We have explored the exposure of relaxing scenarios in immersive Virtual Reality (iVR) as an intervention strategy for people with moderate Alzheimers disease. (2) Methods Three participants were recruited from a day center to participate in a five-week study, which included a Pre- and Post-evaluation with the Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory-Questionnaire (NPI-Q), Clinical Dementia Rating Scale (CDR), Global Deterioration Scale (GDS), Hamilton Anxiety Rating Scale (HARS), State-Trait Anxiety Inventory (STAI), and the anxiety subdomain of the Neuropsychiatric Inventory (NPI). Participants heart rate, oxygen saturation, arterial pressure, and respiratory rate were also monitored during intervention sessions. Three virtual scenarios from Nature Treks VR were used as the intervention over three weeks (a total of nine sessions). (3) Results Post-intervention anxiety assessment showed a light reduction in psychological anxiety in the HARS questionnaire. A light reduction in heart rate was also observed during the exposure to iVR. (4) Discussion The use of virtual scenarios was a satisfactory experience for all the participants. Preliminary data point to a relaxing effect of iVR scenarios and a potential reduction in psychological anxiety, but further research is required to confirm the efficacy of the intervention.

Cognitive and Mood Effect of Alpha-Lipoic Acid Supplementation in a Nonclinical Elder Sample An Open-Label Pilot Study.

Memory disorders are common among elder people, and nonclinical cognitive decline is commonly experienced with age. Preclinical investigations have explored the possible role of alpha-lipoic acid (ALA), a known antioxidant compound abundant in vegetables and animal tissues, in reducing oxidative stress in the aging brain and preventing cognitive decline. However, clinical evidence is limited, and the few existing results are contrasting. In addition, while most of the existing trials have been focused on the effects of ALA administration in Alzheimers disease (AD) or other types of dementia, studies evaluating its effects on nonclinical elder population are still missing. In the present open-label, pilot study, fifteen elder patients (mean age 84.5 ± 5.77) received ALA at a daily dose of 600 mgday for 12 weeks. General cognitive function, executive function, and mood symptom assessment were carried out at baseline and at the endpoint. Overall, ALA administration was generally well-tolerated (only one dropout due to gastrointestinal side effects). However, no statistically significant effects either on cognitive function, executive function, or mood were found. Despite several limitations, our study found no evidence of positive effects on cognition and mood after ALA administration in elder people without the diagnosis of AD or cognitive impairment. Further clinical trials are needed to better investigate ALA effectiveness on cognition and mood in elder subjects.

Links between COVID-19 and Alzheimers Disease-What Do We Already Know

Alzheimers disease (AD) is a life-changing condition whose etiology is explained by several hypotheses. Recently, a new virus contributed to the evidence of viral involvement in AD the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 coronavirus disease. AD was found to be one of the most common COVID-19 comorbidities, and it was found to increase mortality from this disease as well. Moreover, AD patients were observed to present with the distinct clinical features of COVID-19, with delirium being prevalent in this group. The SARS-CoV-2 virus enters host cells through the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is overexpressed in brains with AD, which thus increases the viral invasion. Furthermore, the inhibition of the ACE2 receptor by the SARS-CoV-2 virus may also decrease the brain-derived neurotrophic factor (BDNF), contributing to neurodegeneration. The ApoE ε4 allele, which increases the risk of AD, was found to facilitate the SARS-CoV-2 entry into cells. Furthermore, the neuroinflammation and oxidative stress existing in AD patients enhance the inflammatory response associated with COVID-19. Moreover, pandemic and associated social distancing measures negatively affected the mental health, cognitive function, and neuro-psychiatric symptoms of AD patients. This review comprehensively covers the links between COVID-19 and Alzheimers disease, including clinical presentation, molecular mechanisms, and the effects of social distancing.

A Deep Learning Approach to Predict Chronological Age.

Recently, researchers have turned their focus to predicting the age of people since numerous applications depend on facial recognition approaches. In the medical field, Alzheimers disease mainly depends on patients ages. Multiple methods have been implemented and developed to predict age. However, these approaches lack accuracy because every image has unique features, such as shape, pose, and scale. In Saudi Arabia, Vision 2030, concerning the quality of life, is one of the twelve initiatives that were launched recently. The health sector has gained increasing attention as the government has introduced age-based policies to improve the health of its elderly residents. These residents are urgently advised to vaccinate against COVID-19 based on their age. In this paper, proposing a practical, consistent, and trustworthy method to predict age is presented. This method uses the color intensity of eyes and a Convolutional Neural Network (CNN) to predict age in real time based on the ensemble of CNN. A segmentation algorithm is engaged since the approach takes its input from a video stream or an image. This algorithm extracts data from one of the essential parts of the face the eyes. This part is also informative. Several experiments have been conducted on MATLAB to verify and validate results and relative errors. A Kaggle website dataset is utilized for ages 4 to 59. This dataset includes over 270,000 images, and its size is roughly 2 GB. Consequently, the proposed approach produces ±8.69 years of Mean Square Error (MSE) for the predicted ages. Lastly, a comparative evaluation of relevant studies and the presented algorithm in terms of accuracy, MSE, and Mean Absolute Error (MAE) is also provided. This evaluation shows that the approach developed in the current study outperforms all considered performance metrics since its accuracy is 97.29%. This study found that the color intensity of eyes is highly effective in predicting age, given the high accuracy and acceptable MSE and MAE results. This indicates that it is helpful to utilize this methodology in real-life applications.

Computer-Based Cognitive Training vs. Paper-and-Pencil Training for Language and Cognitive Deficits in Greek Patients with Mild Alzheimers Disease A Preliminary Study.

The purpose of the present study was to explore whether Computer-Based Cognitive Training (C-BCT) versus Paper-Pencil Cognitive Training (P-PCT) is more beneficial in improving cognitive and language deficits in Greek patients living with Alzheimers disease (pwAD). Twenty pwAD were assigned to two groups (a) the C-BCT group, receiving a computer-based cognitive training program using the RehaCom software, and (b) the P-PCT group, which received cognitive training using paper and pencil. The cognitive training programs lasted 15 weeks and were administered twice a week for approximately one hour per session. The analyses of each groups baseline versus endpoint performance demonstrated that the P-PCT group improved on delayed memory, verbal fluency, attention, processing speed, executive function, general cognitive ability, and activities of daily living. In contrast, the C-BCT group improved on memory (delayed and working), naming, and processing speed. Comparisons between the two groups (C-BCT vs. P-PCT) revealed that both methods had significant effects on patients cognition, with the P-PCT method transferring the primary cognitive benefits to real-life activities. Our findings indicate that both methods are beneficial in attenuating cognitive and language deficits in pwAD. The need for large-scale neurobehavioral interventions to further clarify this issue, however, remains a priority.

The Pursuit of the Inside of the Amyloid Hypothesis-Is C99 a Promising Therapeutic Target for Alzheimers Disease

Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimers disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-β (Aβ), which accumulates in the patient brain. The amyloid hypothesis based therapy that places the aggregation and toxicity of Aβ at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. Aβ is produced from a type-I transmembrane protein, Aβ precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called βCTF), is a direct precursor of Aβ and accumulates in the AD patients brain to demonstrate toxicity independent of Aβ. Conventional drug discovery strategies have focused on Aβ toxicity on the outside of the neuron, but C99 accumulation might explain the toxicity on the inside of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aβ is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis.

The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.

Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut-brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.

The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimers Disease.

Modeling Alzheimers disease (AD) using human-induced pluripotent stem cells (iPSCs) is a field now spanning 15 years. Developments in the field have shown a shift in using simple 2D cortical neuron models to more advanced tri-cultures and 3D cerebral organoids that recapitulate more features of the disease. This is largely due to development and optimization of new cell protocols. In this review, we highlight recent major breakthroughs in the AD field and the implications this has in modeling AD using iPSCs (AD-iPSCs). To date, AD-iPSCs have been largely used to recapitulate and study impaired amyloid precursor protein (APP) processing and tau phosphorylation in both familial and sporadic AD. AD-iPSCs have also been studied for varying neuronal and glial dysfunctions. Moreover, they have been useful for discovering new molecular mechanisms, such as identifying proteins that bridge APP processing with tau phosphorylation and for identifying molecular pathways that bridge APP processing dysfunction with impaired cholesterol biosynthesis. Perhaps the greatest use of AD-iPSCs has been in discovering compounds via drug screening, that reduce amyloid beta (Aβ) in neurons, such as the anti-inflammatory compound, cromolyn, and antiparasitic drugs, avermectins. In addition, high content screening using AD-iPSCs has led to the identification of statins that can reduce levels of phosphorylated tau (p-Tau) in neurons. Some of these compounds have made it through to testing in human clinical trials. Improvements in omic technologies including single cell RNA sequencing and proteomics as well as advances in production of iPSC-cerebral organoids and tri-cultures is likely to result in the further discovery of new drugs and treatments for AD. Some caveats remain in the field, including, long experimental conditions to create mature neurons, high costs of media that limit research capabilities, and a lack of reproducibility using current iPSC-cerebral organoid protocols. Despite these current limitations, AD-iPSCs remain an excellent cellular model for studying AD mechanisms and for drug discovery.

Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimers Disease.

Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimers disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3KAkt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.

Unraveling Presenilin 2 Functions in a Knockout Zebrafish Line to Shed Light into Alzheimers Disease Pathogenesis.

Mutations in presenilin 2 (PS2) have been causally linked to the development of inherited Alzheimers disease (AD). Besides its role as part of the γ-secretase complex, mammalian PS2 is also involved, as an individual protein, in a growing number of cell processes, which result altered in AD. To gain more insight into PS2 (dys)functions, we have generated a

An Approach toward Artificial Intelligence Alzheimers Disease Diagnosis Using Brain Signals.

Electroencephalography (EEG) signal analysis is a rapid, low-cost, and practical method for diagnosing the early stages of dementia, including mild cognitive impairment (MCI) and Alzheimers disease (AD). The extraction of appropriate biomarkers to assess a subjects cognitive impairment has attracted a lot of attention in recent years. The aberrant progression of AD leads to cortical detachment. Due to the interaction of several brain areas, these disconnections may show up as abnormalities in functional connectivity and complicated behaviors. This work suggests a novel method for differentiating between AD, MCI, and HC in two-class and three-class classifications based on EEG signals. To solve the class imbalance, we employ EEG data augmentation techniques, such as repeating minority classes using variational autoencoders (VAEs), as well as traditional noise-addition methods and hybrid approaches. The power spectrum density (PSD) and temporal data employed in this studys feature extraction from EEG signals were combined, and a support vector machine (SVM) classifier was used to distinguish between three categories of problems. Insufficient data and unbalanced datasets are two common problems in AD datasets. This study has shown that it is possible to generate comparable data using noise addition and VAE, train the model using these data, and, to some extent, overcome the aforementioned issues with an increase in classification accuracy of 2 to 7%. In this work, using EEG data, we were able to successfully detect three classes AD, MCI, and HC. In comparison to the pre-augmentation stage, the accuracy gained in the classification of the three classes increased by 3% when the VAE model added additional data. As a result, it is clear how useful EEG data augmentation methods are for classes with smaller sample numbers.

R4Alz-Revised A Tool Able to Strongly Discriminate Subjective Cognitive Decline from Healthy Cognition and Minor Neurocognitive Disorder.

The diagnosis of the minor neurocognitive diseases in the clinical course of dementia before the clinical symptoms appearance is the holy grail of neuropsychological research. The R4Alz battery is a novel and valid tool that was designed to assess cognitive control in people with minor cognitive disorders. The aim of the current study is the R4Alz batterys extension (namely R4Alz-R), enhanced by the design and administration of extra episodic memory tasks, as well as extra cognitive control tasks, towards improving the overall R4Alz discriminant validity. The study comprised 80 people (a) 20 Healthy adults (HC), (b) 29 people with Subjective Cognitive Decline (SCD), and (c) 31 people with Mild Cognitive Impairment (MCI). The groups differed in age and educational level. Updating, inhibition, attention switching, and cognitive flexibility tasks discriminated SCD from HC ( SCD seems to be stage a of neurodegeneration since it can be objectively evaluated via the R4Alz-R battery, which seems to be a useful tool for early diagnosis.

Application of the AT(N) and Other CSF Classification Systems in Behavioral Variant Frontotemporal Dementia.

Patients with a frontotemporal lobar degeneration (FTLD) usually manifest with behavioral variant frontotemporal dementia (bvFTD). Alzheimers disease (AD) may also manifest with a predominant behavioral-dysexecutive syndrome, similar to bvFTD. Cerebrospinal fluid (CSF) biomarkers, such as total tau (τ A total of 105 bvFTD patients (21 possible bvFTD 20%) with CSF data, examined from 2008 to 2022, were included. Seventy-eight AD patients and 62 control subjects were included. The CSF biomarkers were measured with Innotest (2008-2017 subcohort) and EUROIMMUN (2017-2022 subcohort) ELISAs. Depending on the classification system, 7.6 to 28.6% of bvFTD had an AD biochemical profile. The τ The four classification criteria of CSF AD biomarkers resulted in differences in AD allocation in this bvFTD cohort. A consensus on the optimal classification criteria of CSF AD biomarkers is pivotal.

Computer-Aided Screening and Revealing Action Mechanism of Green Tea Polyphenols Intervention in Alzheimers Disease.

The accumulation of cross-β-sheet amyloid fibrils is a hallmark of the neurodegenerative process of Alzheimers disease (AD). Although it has been reported that green tea substances such as epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) could alleviate the symptoms of AD and other neurodegenerative diseases, the pharmacological mechanism remains largely unexplored. This study aimed to reveal the underlying mechanism of EC, ECG, EGC and EGCG in AD using a computer-aided screening strategy. Our results showed that the four tea polyphenols interfered with the signaling pathways of AD via calcium signaling channels, neurodegeneration-multiple disease signal pathways and others. We also identified the key residues of the interaction between VEGFA and the four active components, which included Glu64 and Phe36. Overall, we have provided valuable insights into the molecular mechanism of tea polyphenols, which could be used as a reference to improve therapeutic strategies against AD.

Cultivation Factors That Affect Amyloid-β Aggregation Inhibitory Activity in

Alzheimers disease (AD) is thought to be caused by the deposition of amyloid-β (Aβ) in the brain. Aβ begins to aggregate approximately 20 years before the expression of its symptoms. Previously, we developed a microliter-scale high-throughput screening (MSHTS) system for inhibitors against Aβ aggregation using quantum dot nanoprobes. Using this system, we also found that plants in the

Neural biomarker diagnosis and prediction to mild cognitive impairment and Alzheimers disease using EEG technology.

Electroencephalogram (EEG) has emerged as a non-invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimers disease (AD). However, the effectiveness of EEG in the precise diagnosis and assessment of AD and its preclinical stage, amnestic mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD. A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting-state EEG recordings for a three-level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of models by combining participants EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for assessing the disease progression and individuals cognitive function. The identified EEG biomarkers achieved over 70% accuracy in the three-level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD-linked neurodegeneration on EEG metrics were localized at parieto-occipital regions. In the cross-validation predictive analyses, the optimal EEG features were more effective than the CSF APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG CSF APOE measures achieved the best performance for all targets of prediction. Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.

Neuroprotective activity of novel phenanthrene derivative from Grewia tiliaefolia by in vitro and in silico studies.

Medicinal plants possess range of phytochemicals accountable for their diverse biological activities. Presently, such compounds have been isolated from medicinal plants, characterized and evaluated for their pharmacological potential. In the present study, the efforts have been made to isolate the compound(s) from Grewia tiliaefolia Vahl., plant known for its ameliorative effect on brain related diseases such as anxiety, depression, cognitive disorders and Parkinsons disease. Plant extract was subjected to isolation of compound(s) using column chromatography and isolated compound was characterized by NMR FTIR and LCMS. The isolated compound was novel with the IUPAC name of the compound is propyl 3-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentaaphenanthrene-17-carboxylate, designated as A-1 and has not been reported before. A-1 was further evaluated for its antioxidant potential using in vitro antioxidant assays (2,2-diphenyl-1-picryl-hydrazyl-hydrate, DPPH assay and reducing power assay, RPA). Also, Acetylcholinesterase (AChE) inhibitory potential of A-1 and extract was analysed. Results showed that A-1 exhibited significantly higher antioxidant activity in both DPPH and RPA assay as compared to plant extract. In case of AChE inhibitory activity again, A-1 has shown significantly higher activity as compared to plant extract. In silico study was conducted to predict its action on proteins playing crucial role in neurological and neurodegenerative disorders such as gamma amino butyric acid (GABA) receptor and glutamate α amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu AMPA) receptor in epilepsy and AChE enzyme in Alzheimers diseases. The compound has shown interaction in following order AChE > GABA receptor > Glu AMPA receptor. Further, molecular dynamic simulations and ADME studies of A-1 and AChE enzyme revealed that A-1 yielded good results in all parameters and hence can relieve Alzheimers like symptoms.

Evidence from ClinicalTrials.gov on the growth of Digital Health Technologies in neurology trials.

Digital Health Technologies (DHTs) such as connected sensors offer particular promise for improving data collection and patient empowerment in neurology research and care. This study analyzed the recent evolution of the use of DHTs in trials registered on ClinicalTrials.gov for four chronic neurological disorders epilepsy, multiple sclerosis, Alzheimers, and Parkinsons disease. We document growth in the collection of both more established digital measures (e.g., motor function) and more novel digital measures (e.g., speech) over recent years, highlighting contexts of use and key trends.

Forecasting individual progression trajectories in Alzheimers disease.

The anticipation of progression of Alzheimers disease (AD) is crucial for evaluations of secondary prevention measures thought to modify the disease trajectory. However, it is difficult to forecast the natural progression of AD, notably because several functions decline at different ages and different rates in different patients. We evaluate here AD Course Map, a statistical model predicting the progression of neuropsychological assessments and imaging biomarkers for a patient from current medical and radiological data at early disease stages. We tested the method on more than 96,000 cases, with a pool of more than 4,600 patients from four continents. We measured the accuracy of the method for selecting participants displaying a progression of clinical endpoints during a hypothetical trial. We show that enriching the population with the predicted progressors decreases the required sample size by 38% to 50%, depending on trial duration, outcome, and targeted disease stage, from asymptomatic individuals at risk of AD to subjects with early and mild AD. We show that the method introduces no biases regarding sex or geographic locations and is robust to missing data. It performs best at the earliest stages of disease and is therefore highly suitable for use in prevention trials.

Advocating for a dementia-inclusive visual communication.

This study examines the underlying visual communication strategies found in existing images of dementia in the public domain. By delineating how experiences of dementia are visualized and their consequent social interpretations, we aim to inform and advocate for a dementia-inclusive visual communication, that is, visual depictions that cultivate and represent a dementia-inclusive society. The visuals were analyzed by employing the Visual Discourses of Disability (ViDD) framework that juxtaposes the There is a predominance of stigmatized images, constructing dementia as a loss and deficit, thus depicting individuals in distanced suffering. Generic representations of people through stock images, a unique focus on the hands, representations of brain degeneration through abstractions and missing puzzle pieces are also prevalent. Despite these, the interview data confirmed that the When capturing, selecting and publishing images of dementia, organizations should deliberate on different visual elements which evoke

DNAzyme-driven bipedal DNA walker triggered to hybridize silver nanoparticle probes for electrochemical detection of amyloid-β oligomer.

Amyloid-β oligomer has been considered as a promising molecular biomarker for the diagnosis of Alzheimers disease due to their significant neural synapse toxicity. Therefore, it is essential to create an easy approach for the selective detection of Amyloid-β oligomer that has high sensitivity and cheap cost. In this work, we developed an innovative enzyme-free electrochemical aptasensor based on the DNAzyme-driven DNA bipedal walker tactics for sensing Amyloid-β oligomer. Bipedal DNA walkers demonstrate a wider walking region, better walking kinetics, and higher amplification effectiveness than typical DNA walkers. The Mg

Mitochondria are highly dynamic organelles known to play role in the regulation of several cellular biological processes. However, their dynamics such as number, shape, and biological functions are regulated by mitochondrial fusion and fission process. The balance between the fusion and fission process is most important for the maintenance of mitochondrial structure as well as cellular functions. The alterations within mitochondrial dynamic processes were found to be associated with the progression of neurodegenerative diseases. In recent years, mitofusin-2 (Mfn2), a GTPase has emerged as a multifunctional protein which not only is found to regulate the mitochondrial fusion-fission process but also known to regulate several cellular functions such as mitochondrial metabolism, cellular biogenesis, signalling, and apoptosis via maintaining the ER-mitochondria contact sites. In this review, we summarize the current knowledge of the structural and functional properties of the Mfn2, its transcriptional regulation and their roles in several cellular functions with a focus on current advances in the pathogenesis of neurodegenerative diseases.

Reduced SUMOylation of Nrf2 signaling contributes to its inhibition induced by amyloid-β.

Oxidative stress induced by amyloid-β (Aβ) has been considered as one of the important mechanisms in the development of Alzheimer disease (AD). The inhibition of endogenous antioxidant Nrf2 signaling in the brain of AD patients aggravates the oxidative damage, however, the causes of Nrf2 signaling inhibition are unclear. It is reported that smallubiquitin-like modification (SUMOylation) is involved in the process of oxidative injury. To investigate whether and how SUMOylation was involved in the inhibition of Nrf2 signaling pathway induced by Aβ, Aβ intrahippocampal injection rat model and Aβ treated SH-SY5Y cell model were used in the current study. Small interfering RNA and lentivirus transfection were used to intervene SUMOylation, and the level of SUMOylation was assessed by immunoprecipitation. The present in vivo and in vitro studies revealed that SUMOylation levels of Nrf2 and MafF, as well as the overall SUMOylation level were reduced under long-term Aβ insult. Meanwhile, the binding of Nrf2 to MafF was decreased, accompanied by low interaction with antioxidant response element (ARE) area of gene. Down-regulation of SUMO protein exacerbated the Aβ-induced inhibition of Nrf2 signaling pathway, while, enhancement of SUMOylation of Nrf2 and MafF by overexpression of Ubc9 reversed this process. These results imply that reduction in SUMOylation induced by Aβ contributed to the inhibition of Nrf2 signaling, and SUMOylation might be a potential therapeutic target of AD.

The neuroprotective effect of ginsenoside Rb1 on the cerebral cortex changes induced by aluminium chloride in a mouse model of Alzheimers disease A histological, immunohistochemical, and biochemical study.

Alzheimers disease (AD) is one of the most common types of dementia among neurodegenerative disorders characterized by attention deficits and memory loss. Panax ginseng is a traditional Chinese herbal remedy that has been employed for millennia to manage dementia linked with aging and memory impairment. Ginsenoside Rb1 is one of Panax ginsengs most abundant components. The present work evaluated the neuroprotective effects of ginsenoside Rb1 on the cerebral cortex of AlCl

Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration.

The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood-brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimers disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration.

BMP4-SMAD159-RUNX2 pathway activation inhibits neurogenesis and oligodendrogenesis in Alzheimers patients iPSCs in senescence-related conditions.

In addition to increasing β-amyloid plaque deposition and tau tangle formation, inhibition of neurogenesis has recently been observed in Alzheimers disease (AD). This study generated a cellular model that recapitulated neurogenesis defects observed in patients with AD, using induced pluripotent stem cell lines derived from sporadic and familial AD (AD iPSCs). AD iPSCs exhibited impaired neuron and oligodendrocyte generation when expression of several senescence markers was induced. Compound screening using these cellular models identified three drugs able to restore neurogenesis, and extensive morphological quantification revealed cell-line- and drug-type-dependent neuronal generation. We also found involvement of elevated Sma- and Mad-related protein 159 (SMAD159) phosphorylation and greater Runt-related transcription factor 2 (RUNX2) expression in neurogenesis defects in AD. Moreover, BMP4 was elevated in AD iPSC medium during neural differentiation and cerebrospinal fluid of patients with AD, suggesting a BMP4-SMAD159-RUNX2 signaling pathway contribution to neurogenesis defects in AD under senescence-related conditions.

Donepezil halts acetic acid-induced experimental colitis in rats and its associated cognitive impairment through regulating inflammatoryoxidativeapoptotic cascades An add-on to its anti-dementia activity.

Ulcerative colitis (UC) is a persistent inflammatory bowel disease (IBD) that is regarded as a risk factor for cognitive impairment. Donepezil (DON), a centrally acting acetylcholinesterase inhibitor (AChEI), is approved for the management of Alzheimers disease (AD). We aimed to scrutinize the impact of DON on acetic acid (AA)-induced UC in rats and to evaluate its ability to attenuate inflammatory response, oxidative strain, and apoptosis in this model and its associated cognitive deficits. Rats were categorized into normal, DON, AA, and AA DON groups. DON (5 mgkgday) was administered orally for 14 days either alone or beginning with the day of UC induction. Colitis was evoked by a single transrectal injection of 1 ml of 4 % acetic acid. Results revealed that DON significantly improved the behavioral abnormalities with the mitigation of inflammation, apoptosis, and histopathological changes in the hippocampi of the colitis group. Moreover, DON significantly alleviated the macroscopic and microscopic changes associated with colitis. Interestingly, DON inhibited pro-inflammatory cytokines via suppression of AA-induced activation of nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in the colon, along with serum IL-1β. DON inhibited colon lipid peroxidation, restored the antioxidants with a significant amelioration of the degree of neutrophil infiltration, and repressed colitis-induced matrix metalloproteinases-9 (MMP-9) production. Furthermore, DON decreased the BaxBcl-2 ratio and caspase-3 protein expressions. Eventually, in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells, DON suppressed nitric oxide (NO) release, demonstrating the ability of DON to significantly curtail inflammation in immune cells. Taken together, DON ameliorated experimental colitis and its linked cognitive dysfunction, possibly via its antioxidant effect and modulation of pro-inflammatory cytokines and apoptosis. Thereby, DON could be a therapeutic nominee for UC and associated neurological disorders.

Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.

Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimers disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (

Assessing What Matters to People Affected by Alzheimers Disease A Quantitative Analysis.

In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimers disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD. We administered a web-based survey to individuals at risk for or with AD (Group 1 unimpaired cognition with evidence of AD pathology Group 2 AD risk factors and subjective cognitive complaintsmild cognitive impairment Group 3 mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 (not at all important) to 5 (extremely important). Among the 274 respondents (70.4% female 63.1% white), over half of patient respondents rated all 42 items as very important or extremely important, while care partners rated fewer items as very important or extremely important. Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6), indicating that all items were at least moderately to very important. Among care partners of people with moderate or severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4), indicating that most items were rated as at least moderately important. Overall, taking medications correctly, not feeling down or depressed, and staying safe had the highest importance ratings among both patients and care partners, regardless of AD phase. Concepts of importance to individuals affected by AD go beyond the common understanding of cognition or function alone, reflecting a desire to maintain independence, overall physical and mental health, emotional well-being, and safety. Preservation of these attributes may be key to understanding whether interventions deliver clinically meaningful outcomes.

Global ambient particulate matter pollution and neurodegenerative disorders a systematic review of literature and meta-analysis.

Previous studies on particulate matter (PM) exposure and neurodegenerative disorders showed inconsistent results, and few studies systematically examined the long-term effect of PM on neurodegenerative diseases, including all-cause dementia, Alzheimers disease, Parkinsons disease, vascular dementia, amyotrophic lateral sclerosis, and cognitive function decline. We systematically searched for published studies in PubMed, Embase, Cochrane Library, and Web of Science up to October 31, 2022. To facilitate a comparison of effect sizes from different studies, we standardized units across studies to a 10 μgm

Early identification of seizure freedom with medical treatment in patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is usually associated with a poor response to antiseizure medications. We focused on MTLE-HS patients who were seizure free on medication to (1) determine the clinical factors associated with seizure freedom and (2) develop a machine-learning classifier to better earlier identify those patients. We performed a retrospective, multicentric study comparing 64 medically treated seizure-free MTLE-HS patients with 200 surgically treated drug-resistant MTLE-HS patients. First, we collected medical history and seizure semiology data. Then, we developed a machine-learning classifier based on clinical data. Medically treated seizure-free MTLE-HS patients were seizure-free for at least 2 years, and for a median time of 7 years at last follow-up. Compared to drug-resistant MTLE-HS patients, they exhibited an older age at epilepsy onset (22.5 vs 8.0 years, p < 0.001), a lesser rate of febrile seizures (39.0% vs 57.5%, p 0.035), focal aware seizures (previously referred to as aura)(56.7% vs 90.0%, p < 0.001), autonomic focal aware seizures in presence of focal aware seizure (17.6% vs 59.4%, p < 0.001), dystonic posturing of the limbs (9.8% vs 47.0%, p < 0.001), gestural (27.4% vs 94.0%, p < 0.001), oro-alimentary (32.3% vs 75.5%, p < 0.001) or verbal automatisms (12.9% vs 36.0%, p 0.001). The classifier had a positive predictive value of 0.889, a sensitivity of 0.727, a specificity of 0.962, a negative predictive value of 0.893. Medically treated seizure-free MTLE-HS patients exhibit a distinct clinical profile. A classifier built with readily available clinical data can identify them accurately with excellent positive predictive value. This may help to individualize the management of MTLE-HS patients according to their expected pharmacosensitivity.

Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β.

Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimers disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function due to APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not due to differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism on neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.

Brain perfusion, cognition, and plasma Alzheimers biomarkers in moyamoya disease.

Because growing interest has been focusing on cerebral blood flow (CBF) to predict, prevent, and treat Alzheimers disease (AD), it is important to clarify the role of CBF in AD pathology and cognitive decline. In a moyamoya disease (MMD) cohort, we examined CBF, specific cognitive domains, and plasma AD biomarkers, as well as correlations among these variables. CBF was significantly reduced in newly diagnosed MMD patients, while plasma phosphorylated tau181 was elevated and positively correlated with hypoperfusion accumulation. MMD patients scored significantly lower than controls in multiple cognitive tests. Revascularization increased CBF to the recipient brain territories as well as cognitive performance but produced no significant change in AD biomarker levels. These data suggest a link between accumulated reductions in CBF and cognitive decline, as well as a possible role of AD-like pathological burden. Further studies in MMD will provide opportunities to explore new treatment strategies.

Rheumatic manifestations of Parkinsons disease an overview.

Parkinsons disease is the second most common neurodegenerative disorder after Alzheimers disease. It can be responsible for several rheumatological manifestations. This article aimed to review and summarize current knowledge on musculoskeletal diseases associated with Parkinsons disease and their management. We conducted a narrative review of musculoskeletal features associated with Parkinsons disease. Rheumatological manifestations of Parkinsons disease include postural disorders (antecollis, cervical kyphosis, cervical positive sagittal malalignment, camptocormia, Pisa syndrome, scoliosis), bone disorders (osteoporosis, bone fractures), and joint disorders (frozen shoulder, hand, and foot deformities). Rheumatological manifestations lead to physical disability, long-term pain, and impaired quality of life. However, the management of these manifestations is not yet codified. It can associate botulinum toxin, thoraco-pelvic anterior distraction, orthosis, orthopedic surgical correction, pallidotomy, or deep brain stimulation in patients with camptocormia. Therapeutic management of osteoporosis includes calcium and vitamin D intake and bisphosphonates. Rheumatological manifestations are common in Parkinsons disease. Optimal care of patients with Parkinsons disease should include attention to management of postural, bone, and joint disorders since it remains a major cause of functional impairment and disability.

MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging.

White matter damage is a feature of Alzheimers disease, yet little is known about how facets of the Alzheimers disease process relate to key features of white matter structure. We examined the association of Alzheimers disease (Aß Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction MWF) and axonal density (defined by neurite density index NDI), we quantified plasma levels of Aβ In total, 119 participants received MWF imaging (age 56 SD 21), of which 43 received NDI imaging (age 50 SD 18). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß -0.13 P 0.049). Further, higher levels of NfL (ß -0.22 P 0.009) and GFAP (ß -0.29 P 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aβ Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region-specific myelin content. Axonal loss and demyelination may co-occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.

Cohort study of the effects of occupation and environmental tobacco smoke on the incidence of Alzheimers disease among seniors.

Alzheimers disease (AD) is a disease caused by many factors including occupational and environmental factors. Secondhand smoke (SHS) can affect cognitive function. However, there is limited recent epidemiological research on how SHS and occupational factors affect AD in Zhejiang province. We established a cohort of an AD high-risk population. In 2018, a cohort of 1742 elderly aged ≥60 years was established. In 2020, the cohort was followed up, and a total of 1545 people participated in the two surveys. Data collection included demographic and economic information such as age, gender, occupation, education level etc., and relative health behavior information such as smoking, drinking and tea drinking, etc. Basic physical examination data included height, weight, blood pressure, etc. At the same time, related cognitive status was assessed. Cox proportional hazards regression models, both unadjusted and adjusted models, were used to determine associations between cohort characteristics and AD. The results showed that SHS exposure and occupational characteristics were associated with an increased risk of cognitive impairments in seniors. Subgroups who used to work as blue-collar workers, who never worked, who kept standing for most of the time at work, and who were engaged in hard physical labor prior to retirement, had high incidence rates of AD. It was revealed that SHS, standing for most of the time and hard physical labor were associated risk factors of AD among seniors, compared with white-collar work. We recommend that the government establish a community supervisory mechanism to persuade smokers to quit or control smoking.

Effects of electroacupuncture on urinary metabolome and microbiota in presenilin12 conditional double knockout mice.

The treatment of Alzheimers disease (AD) is still a worldwide problem due to the unclear pathogenesis and lack of effective therapeutic targets. In recent years, metabolomic and gut microbiome changes in patients with AD have received increasing attention, and the microbiome-gut-brain (MGB) axis has been proposed as a new hypothesis for its etiology. Considering that electroacupuncture (EA) efficiently moderates cognitive deficits in AD and its mechanisms remain poorly understood, especially regarding its effects on the gut microbiota, we performed urinary metabolomic and microbial community profiling on EA-treated AD model mice, presenilin 12 conditional double knockout (PS cDKO) mice, to observe the effect of EA treatment on the gut microbiota in AD and find the connection between affected gut microbiota and metabolites. After 30 days of EA treatment, the recognition memory ability of PS cDKO mice was evaluated by the Y maze and the novel object recognition task. Urinary metabolomic profiling was conducted with the untargeted GC-MS method, and 16S rRNA sequence analysis was applied to analyze the microbial community. In addition, the association between differential urinary metabolites and gut microbiota was clarified by Spearmans correlation coefficient analysis. In addition to reversed cognitive deficits, the urinary metabolome and gut microbiota of PS cDKO mice were altered as a result of EA treatment. Notably, the increased level of isovalerylglycine and the decreased levels of glycine and threonic acid in the urine of PS cDKO mice were reversed by EA treatment, which is involved in glyoxylate and dicarboxylate metabolism, as well as glycine, serine, and threonine metabolism. In addition to significantly enhancing the diversity and richness of the microbial community, EA treatment significantly increased the abundance of the genus Electroacupuncture alleviates cognitive deficits in AD by modulating gut microbiota and metabolites.

The amyloid imaging for the prevention of Alzheimers disease consortium A European collaboration with global impact.

Amyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimers disease (AD). The Amyloid Imaging to Prevent Alzheimers Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and Small and Medium-sized enterprises (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population. In the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with AMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BP The AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

Cationic biopolymer decorated Asiatic Acid and

Aerobic exercise does not affect serum neurofilament light in patients with mild Alzheimers disease.

Aerobic exercise has been shown to modify Alzheimer pathology in animal models, and in patients with multiple sclerosis to reduce neurofilament light (NfL), a biomarker of neurodegeneration. To investigate whether a 16-week aerobic exercise program was able to reduce serum NfL in patients with mild Alzheimers disease (AD). This is a secondary analysis of data from the multi-center Preserving Cognition, Quality of Life, Physical Health, and Functional Ability in Alzheimers disease The Effect of Physical Exercise (ADEX) study. Participants were randomized to 16 weeks of moderate intensity aerobic exercise or usual care. Clinical assessment and measurement of serum NfL was done at baseline and after the intervention. A total of 136 participants were included in the analysis. Groups were comparable at baseline except for The findings do not support an effect of the exercise intervention on a single measure of neurodegeneration in AD. Further studies are needed using other types and durations of exercise and other measures of neurodegeneration. clinicaltrials.gov, identifier NCT01681602.

Cerebral blood flow changes induced by high-frequency repetitive transcranial magnetic stimulation combined with cognitive training in Alzheimers disease.

Hypoperfusion of the posterior cingulate cortex (PCC) and precuneus has consistently been reported in patients with Alzheimers disease (AD). Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG) is effective in alleviating the symptoms of patients with mild AD. This study investigated the effects of rTMS-COG therapy on cerebral blood flow (CBF), with a special interest in the PCCprecuneus, and whether observed CBF changes are associated with changes in neuropsychological assessments in AD. Twenty-one patients with mild or moderate AD were randomly divided into real rTMS ( rTMS-COG therapy revealed significant group × time interactions for the Mini-Mental State Examination (F 5.339, Neuropsychological assessments showed immediate and long-term effects on cognitive function and activities of daily living after rTMS-COG therapy. CBF changes induced by high-frequency rTMS-COG therapy are region-dependent, showing immediate effects in the precuneus and long-term effects in the left parahippocampus. These results provide imaging evidence to understand the underlying neurobiological mechanism for the application of rTMS-COG in AD.

Extra cup of tea intake associated with increased risk of Alzheimers disease Genetic insights from Mendelian randomization.

Observational studies report inconclusive effects of tea consumption on the risk of Alzheimers disease (AD), and the mechanisms are unclear. This study aims to investigate the effects of genetically predicted tea intake (cups of tea consumed per day) on AD, brain volume, and cerebral small vessel disease (CSVD) using the two-sample Mendelian randomization (MR) method. Summary statistics of tea intake were obtained from UK Biobank ( In the primary MR analysis, tea intake significantly increased the risk of AD using two different methods (OR This study revealed a potential causal association between per extra cup of tea and an increased risk of AD. Genetically predicted tea intake was associated with a decreased brain volume of gray matter and the right hippocampus, which indicates that over-drinking tea might lead to a decline in language and memory functions. Our results shed light on a novel possible mechanism of tea intake to increase the risk of AD by reducing brain volume.

No genetic causal association between Alzheimers disease and osteoporosis A bidirectional two-sample Mendelian randomization study.

Many observational studies have found an association between Alzheimers disease (AD) and osteoporosis. However, it is unclear whether there is causal genetic between osteoporosis and AD. A two-sample Mendelian randomization (MR) study was used to investigate whether there is a causal relationship between osteoporosis and AD. Genes for osteoporosis and AD were obtained from published the genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) with significant genome-wide differences ( Using the IVW method, MR Egger method, and median-weighted method, we found that the results showed no significant causal effect of osteoporosis at different sites and at different ages on AD, regardless of the removal of potentially pleiotropic SNPs. The results were similar for the opposite direction of causality. These results were confirmed to be reliable and stable by sensitivity analysis. This study found that there is no bidirectional causal relationship between osteoporosis and AD. However, they share similar pathogenesis and pathways.

Urinary protein biomarkers based on LC-MSMS analysis to discriminate vascular dementia from Alzheimers disease in Han Chinese population.

This study aimed to identify the potential urine biomarkers of vascular dementia (VD) and unravel the disease-associated mechanisms by applying Liquid chromatography tandem-mass spectrometry (LC-MSMS). LC-MSMS proteomic analysis was applied to urine samples from 3 groups, including 14 patients with VD, 9 patients with AD, and 21 normal controls (NC). By searching the MS data by Proteome Discoverer software, analyzing the protein abundances qualitatively and quantitatively, comparing between groups, combining bioinformatics analysis using Gene Ontology (GO) and pathway crosstalk analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), and literature searching, the differentially expressed proteins (DEPs) of VD can be comprehensively determined at last and were further quantified by receiver operating characteristic (ROC) curve methods. The proteomic findings showed quantitative changes in patients with VD compared to patients with NC and AD groups among 4,699 identified urine proteins, 939 and 1,147 proteins displayed quantitative changes unique to VD vs. NC and AD, respectively, including 484 overlapped common DEPs. Then, 10 unique proteins named in KEGG database (including PLOD3, SDCBP, SRC, GPRC5B, TSG101STP22VPS23, THY1CD90, PLCD, CDH16, NARSasnS, AGRN) were confirmed by a ROC curve method. Our results suggested that urine proteins enable detection of VD from AD and VC, which may provide an opportunity for intervention.

The effects of cognitive impairment on the multi-scale dynamics of standing postural control during visual-search in older men.

Cognitive impairment disrupts postural control, particularly when standing while performing an unrelated cognitive task (i.e., dual-tasking). The temporal dynamics of standing postural sway are complex, and such complexity may reflect the capacity of the postural control system to adapt to task demands. We aimed to characterize the impact of cognitive impairment on such sway complexity in older adults. Forty-nine older adult males (Alzheimers disease (AD) Repeated-measures ANOVAs revealed significant main effects of group ( AD-related cognitive impairment was associated with a greater relative reduction in postural sway complexity from single- to dual-tasking. Sway complexity appears to be sensitive to the impact of cognitive impairment on standing postural control.

Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimers Disease.

Oxidative stress, inflammation, and amyloid-β are Alzheimers disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-β-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Kochs postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity. Cytosolic oxidatively-damaged mitochondrial DNA accumulated outside mitochondria dose-dependently in preclinical AD and AD patients hippocampal neurons, and in AD patients neocortical neurons but not cerebellar neurons or glia. In oxidatively-stressed neural cells and rodents brains, cytosolic oxidatively-damaged mitochondrial DNA accumulated and increased antiviral and inflammatory proteins, including cleaved caspase-1, interleukin-1β, and interferon-β. Cytosolic double-stranded RNA and DNA are DAMPs that induce antiviral interferons andor inflammatory proteins by oligomerizing with various innate-immune pattern-recognition receptors, e.g., cyclic GMP-AMP synthase and the nucleotide-binding-oligomerization-domain-like-receptor-pyrin-domain-containing-3 inflammasome. In oxidatively-stressed neural cells, cytosolic oxidatively-damaged mitochondrial DNA caused synaptotoxicity and neurotoxicity. Depleting mitochondrial DNA prevented these effects. Additionally, cell-free nucleic acids accumulated in AD patients blood, extracellular vesicles, and senile plaques. Injecting cell-free nucleic acids bound to albumin oligomers into wild-type mices hippocampi triggered antiviral interferon-β secretion interferon-β injection caused synapse degeneration. Deoxyribonuclease-I treatment appeared to improve a severe-AD patients Mini-Mental Status Exam by 15 points. Preclinical and clinical studies of deoxyribonuclease-I and a ribonuclease for AD should be prioritized.

Associations between reproductive history, hormone use,

Relative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimers disease. While womens health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence womens cognition later in life. We investigated the associations between reproductive history, exogenous hormone use, apolipoprotein ( A longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohens Our findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max.

Microglial Activation in Metal Neurotoxicity Impact in Neurodegenerative Diseases.

Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical features, such as Alzheimers and Parkinsons diseases. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several

Mitochondrial calcium cycling in neuronal function and neurodegeneration.

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca

Aqueous extract of Ceratonia siliqua L. leaves elicits antioxidant, anti-inflammatory, and AChE inhibiting effects in amyloid-β42-induced cognitive deficit mice Role of α7-nAChR in modulating Jak2PI3KAktGSK-3ββ-catenin cascade.

Alzheimers disease (AD) is a multifactorial neurodegenerative disorder attributed to several etiological factors including cholinergic dysregulation, neuroinflammation, oxidative stress, β-amyloidogenesis, and tauopathy. This demands the search for multitarget drugs, especially of natural sources owing to their pleiotropic activities and low adverse effects. The present study was conducted to investigate the cognitive-improving potential of Ceratonia siliqua L. (Cs) extract compared with donepezil, an acetylcholinesterase inhibitor, on AD-like pathological alterations induced by single intracerebroventricular amyloid-β42 (Aβ42) injection in mice. Aβ42-injected mice were treated with Cs (100 mgkgday, po) with or without methyllycaconitine (MLA 1 mgkgday, ip), an α7-nAChR antagonist. Aβ42-injected animals demonstrated an elevation of hippocampal Aβ42, p-Tau, and acetylcholinesterase. They also showed a decline in phosphorylated levels of Jak2, PI3K, Akt, and GSK-3β, leading to induction of neuroinflammation and oxidative stress. Noteworthy, Cs improved the histopathological and behavioral variables in addition to mitigating AD hallmarks. It also exerted neuroprotection by reducing NF-κBp65 and TNF-α, while elevating Nrf2 and HO-1, along with stabilizing β-catenin under the impact of Jak2PI3KAktGSK-3β signaling. These beneficial effects of Cs were abrogated by MLA co-administration signifying the α7-nAChR involvement in Cs-mediated effects. Therefore, Cs can ameliorate Aβ42-induced neurodegeneration by modulating Jak2PI3KAktGSK-3ββ-catenin axis in an α7-nAChR-dependent manner.

The Value of Handgrip Strength and Self-Rated Squat Ability in Predicting Mild Cognitive Impairment Development and Validation of a Prediction Model.

Early identification of individuals with mild cognitive impairment (MCI) is essential to combat worldwide dementia threats. Physical function indicators might be low-cost early markers for cognitive decline. To establish an early identification tool for MCI by combining physical function indicators (upper and lower limb function) via a clinical prediction modeling strategy. A total of 5393 participants aged 60 or older were included in the model. The variables selected for the model included sociodemographic characteristics, behavioral factors, mental status and chronic conditions, upper limb function (handgrip strength), and lower limb function (self-rated squat ability). Two models were developed to test the predictive value of handgrip strength (Model 1) or self-rated squat ability (Model 2) separately, and Model 3 was developed by combining handgrip strength and self-rated squat ability. The 3 models all yielded good discrimination performance (area under the curve values ranged from 0.719 to 0.732). The estimated net reclassification improvement values were 0.3279 and 0.1862 in Model 3 when comparing Model 3 to Model 1 and Model 2, respectively. The integrated discrimination improvement values were estimated as 0.0139 and 0.0128 when comparing Model 3 with Model 1 and Model 2, respectively. The model that contains both upper and lower limb function has better performance in predicting MCI. The final prediction model is expected to assist health workers in early identification of MCI, thus supporting early interventions to reduce future risk of AD, particularly in socioeconomically deprived communities.

Does Avoiding Distressing Thoughts and Feelings Influence the Relationship between Carer Subjective Burden and Anxiety Symptoms in Family Carers of People with Dementia

Anxiety remains understudied in family carers of people with dementia. Understanding factors that moderate the relationship between stressors and anxiety symptoms in this population is critical to inform interventions. This study examined whether generic experiential avoidance (AAQ-II) and experiential avoidance specific to caregiving-related thoughts and feelings (EACQ) moderate the relationship between subjective burden (ZBI-12) and anxiety symptoms (GAD-7) in carers of people with dementia. The first model (

Prospective use of amniotic mesenchymal stem cell metabolite products for tissue regeneration.

Chronic disease can cause tissue and organ damage constituting the largest obstacle to therapy which, in turn, reduces patients quality-adjusted life-year. Degenerative diseases such as osteoporosis, Alzheimers disease, Parkinsons disease, and infectious conditions such as hepatitis, cause physical injury to organs. Moreover, damage resulting from chronic conditions such as diabetes can also culminate in the loss of organ function. In these cases, organ transplantation constitutes the therapy of choice, despite the associated problems of immunological rejection, potential disease transmission, and high morbidity rates. Tissue regeneration has the potential to heal or replace tissues and organs damaged by age, disease, or trauma, as well as to treat disabilities. Stem cell use represents an unprecedented strategy for these therapies. However, product availability and mass production remain challenges. A novel therapeutic alternative involving amniotic mesenchymal stem cell metabolite products (AMSC-MP) has been developed using metabolites from stem cells which contain cytokines and growth factors. Its potential role in regenerative therapy has recently been explored, enabling broad pharmacological applications including various gastrointestinal, lung, bladder and renal conditions, as well as the treatment of bone wounds, regeneration and skin aging due to its low immunogenicity and anti-inflammatory effects. The various kinds of growth factors present in AMSC-MP, namely bFGF, VEGF, TGF-β, EGF and KGF, have their respective functions and activities. Each growth factor is formed by different proteins resulting in molecules with various physicochemical properties and levels of stability. This knowledge will assist in the manufacture and application of AMSC-MP as a therapeutic agent.

Somatostatin slows Aβ plaque deposition in aged APP

The neuroendocrine peptide somatostatin (SST) has long been thought of as influencing the deposition of the amyloid β peptide (Aβ) in Alzheimers disease (AD). Missing have been in vivo data in a relevant Aβ amyloidosis model. Here we crossed App