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[Display omitted] • TZ4C treatments alleviated methamphetamine-induced taupathy in SH-SY5Y cells. • TZ4C improved learning and memory deficits in scopolamine-induced rats. • TZ4C decreased AChE activity in the hippocampus of scopolamine-induced rats. • TZ4C significantly reduced the level of p-Tau in the hippocampus of male Wistar rats. • TZ4C reduced cleaved caspase-3/procaspase-3 protein levels both in vitro and in vivo. Alzheimer's disease (AD) is the most common form of neurodegeneration that results in memory disorders and cognitive impairment. The present study investigated the neuroprotective effects of the synthesized thiazolidine-2,4-dione derivative, (E)-5-(4-chlorobenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ4C), an inhibitor of p-Tau and memory impairment, using a SH-SY5Y cell model of methamphetamine-induced tauopathy and a scopolamine-induced memory impairment model in Wistar rats. In the present study, the neuroprotective effect of TZ4C was studied in a SH-SY5Y cellular model of methamphetamine-induced (2 mM) tauopathy and a scopolamine-induced (1.5 mg/kg/day) memory impairment model in male Wistar rats (n = 48). The memory functions and learning abilities of the rats were evaluated using the Morris water maze (MWM) and passive avoidance tests. Additionally, AChE activity in the rat hippocampus was quantified, and the expression of p-Tau, HSP70, and caspase-3 in both in vitro and in vivo samples was evaluated through Western blot analysis. TZ4C (0.1–1000 µM) did not exhibit significantly toxic effects on SH-SY5Y cell viability. Western blot results indicated that TZ4C led to reduced expression of p-Tau, HSP70, and cleaved caspase-3 in SH-SY5Y cells (3 and 10 µM) and the rat hippocampus (2 and 4 mg/kg). Additionally, the findings suggested that TZ4C enhanced memory function in rats with scopolamine-induced impairment and decreased acetylcholinesterase (AChE) specific activity. The comprehensive analysis of in vitro and in vivo experiments underscores the neuroprotective potential (improved neuropathology and reduced memory impairment) of TZ4C. These findings highlight the promise of TZ4C as a candidate for drug discovery programs to identify effective therapies for AD. [ABSTRACT FROM AUTHOR]

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Oddball task-related EEG delta and theta responses are associated with frontal executive functions, which are significantly impaired in patients with dementia due to Parkinson's disease (PDD) and Lewy bodies (DLB). The present study investigated the oddball task-related EEG delta and theta responses in patients with PDD, DLB, and Alzheimer's disease dementia (ADD). During visual and auditory oddball paradigms, EEG activity was recorded in 20 ADD, 17 DLB, 20 PDD, and 20 healthy (HC) older adults. Event-related EEG power spectrum and phase-locking analysis were performed at the delta (1–4 Hz) and theta (4–7 Hz) frequency bands for target and nontarget stimuli. Compared to the HC persons, dementia groups showed lower frontal and central delta and theta power and phase-locking associated with task performance and neuropsychological test scores. Notably, this effect was more significant in the PDD and DLB than in the ADD. In conclusion, oddball task-related frontal and central EEG delta and theta responses may reflect frontal supramodal executive dysfunctions in PDD and DLB patients. • Reduced delta-theta event-related oscillations (EROs) in ADD, PDD, and DLB. • Lower delta and theta EROs in PDD and DLB than ADD. • Reduced frontal supramodal cognitive information processing in PDD and DLB. • Frontal delta-theta EROs reflecting memory and executive functions. [ABSTRACT FROM AUTHOR]

GSDME highly expressed in neurons within the brains of APP23/PS45 mice, which may lead to the dysfunction of neurons. The knockdown of GSDME improved the learning and memory by potentially alleviating the inflammasome response caused by dysfunctional neurons. [Display omitted] • GSDME highly expressed in neurons within the brains of APP23/PS45 mice compared to the age-matched Wild-type mice. • The high expression of GSDME switched apoptosis into pyroptosis cleaved by activated caspase-3 induced by Aβ in vitro. • The knockdown of GSDME improved cognitive disorder of APP23/PS45 by alleviating inflammatory response. Amyloid β protein (Aβ) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aβ induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aβ treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aβ and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is a neurodegenerative disease that commonly occurs in older people. It is characterized by both cognitive and functional impairment. However, as AD has an unclear pathological cause, it can be hard to diagnose with confidence. This is even more so in the early stage of Mild Cognitive Impairment (MCI). This paper proposes a U-Net based Generative Adversarial Network (GAN) to synthesize fluorodeoxyglucose - positron emission tomography (FDG-PET) from magnetic resonance imaging - T1 weighted imaging (MRI-T1WI) for further usage in AD diagnosis including its early-stage MCI. The experiments have displayed promising results with Structural Similarity Index Measure (SSIM) reaching 0.9714. Furthermore, three types of classifiers are developed, i.e., one Multi-Layer Perceptron (MLP) based classifier, two Graph Neural Network (GNN) based classifiers where one is for graph classification and the other is for node classification. 10-fold cross-validation has been conducted on all trials of experiments for classifier comparison. The performance of these three types of classifiers has been compared with the different input modalities setting and data fusion strategies. The results have shown that GNN based node classifier surpasses the other two types of classifiers, and has achieved the state-of-the-art (SOTA) performance with the best accuracy at 90.18% for 3-class classification, namely AD, MCI and normal control (NC) with the synthesized fluorodeoxyglucose - positron emission tomography (FDG-PET) features fused at the input level. Moreover, involving synthesized FDG-PET as part of the input with proper data fusion strategies has also proved to enhance all three types of classifiers' performance. This work provides support for the notion that machine learning-derived image analysis may be a useful approach to improving the diagnosis of AD. [ABSTRACT FROM AUTHOR]

A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with late-onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing, and the resulting isogenic pair of iPSC lines was differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3-dimensional morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMHs) are found on magnetic resonance (MR) images of older individuals and are associated with many neurodegenerative disorders, although the exactrole of WMHs in Alzheimer's disease and other dementias remains an open area of research. Fluid-attenuated inversion recovery (FLAIR) MR imaging sequences show WMHs with good image contrast. Manual segmentation of WMHs on FLAIR images is the widely accepted "gold standard", however, this step is often time-consuming and has a high inter-rater variability. The absence of an automated, robust and accurate approach to segment WMHs remains a processing bottleneck. We explored convolutional neural networks (CNNs) for performing semantic segmentation of WMHs in FLAIR images. Two sets of experiments were conducted: (1) Variations of U-shaped CNNs (U-Nets) were evaluated in 186 individuals, specifically, four architectures (VGG16, VGG19, ResNet152 and EfficientNetB0) having three dimensionalities (2D, 2.5D and 3D). (2) New data from 60 individuals were added to test the generalizability of U-Net, LinkNet and Feature-Pyramid Network (FPN) variants. The first experiment showed that the 2.5D implementation with VGG16 or VGG19 was the most suitable configuration when segmenting WMH (F-measure > 95% and intersection-over-union > 90%). The second experiment confirmed generalizability of these variants when using unprocessed FLAIR images. [Display omitted] • Identification of the best feature-extracting architecture (VGG16 or VGG19) for WHM segmentation. • Identification of the best processing dimensionality implementation (2.5D) for WMH segmentation. • Demonstration of automatic segmentation and labeling of the WMH volume for the whole brain. • Confirmation of the generalizability of several CNN models (U-Net, LinkNet, FPN). [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an incurable, age-related and progressive neurodegenerative disease characterized by cognitive impairments. Deficits in synaptic plasticity were reported in various models of AD-like pathology and are considered as an early contributing factor of cognitive impairment. However, the majority of previous studies were focused on overt, symptomatic stages of pathology and assessed long-term potentiation (LTP), whereas long-term depression (LTD) was much less investigated and the precise nature of its involvement remains poorly defined. To better understand the earliest synaptic dysfunctions along the pre-symptomatic stage of AD-like pathology, we performed a detailed analysis of underlying mechanisms and quantified basal synaptic activity, presynaptic release probability, and synaptic plasticity such as post-tetanic potentiation (PTP), as well as LTP and LTD. These parameters were studied in APPPS1 mouse model at two time points (early- and mid-) along the pre-symptomatic stage, which were compared with alterations monitored at two later time-points, i.e. the onset of cognitive deficits and the overt stage of full-blown pathology. Because sex is known to be an instrumental biological parameter in AD pathophysiology, all alterations were assessed in both males and females. Our data show that, as compared to wild-type (WT) littermates, initial neuronal hyperexcitability, seen at early pre-symptomatic stage shifts subsequently towards hypoexcitability at mid-pre-symptomatic stage and remains impaired at advanced stages. The pre-symptomatic changes also involve increased synaptic plasticity as assessed by paired-pulse facilitation (PPF), which returns to basal level at the onset of pathology and remains stable afterwards. Synaptic plasticity is impaired by mid-pre-symptomatic stage and manifests as lowered LTP and absence of LTD induction, the latter being reported here for the first time. Observed LTP and LTD impairments both persist in older APPPS1 mice. Remarkably, none of the observed differences was gender-dependent. Altogether, our data evidence that major impairments in basal synaptic efficacy and plasticity are detectable already during mid-pre-symptomatic stage of AD-like pathogenesis and likely involve hyperexcitability as the underlying mechanism. Our study also uncovers synaptic alterations that may become critical read-outs for testing the efficiency of novel, pre-symptomatic stage-targeted therapies for AD. • Alzheimer's Disease (AD) displays a long pre-symptomatic stage (PSS). • AD is still incurable since treated late and targeting PSS may be more efficient. • PSS is impossible to assess in human and requires models to identify early targets. • Using a mouse AD model, we identified a novel marker of PSS synaptic dysfunction. • This marker can serve as a read-out for testing efficacy of PSS-targeted therapies. [ABSTRACT FROM AUTHOR]

• PZP is downregulated in diabetes, obesity, and metabolic dysfunction-associated fatty liver disease. • High PZP improve dysregulation of glucose and lipid metabolism. • PZP is reduced in breast cancer, hepatocellular carcinoma, and lung adenocarcinoma. • PZP is elevated in diabetics with lung adenocarcinoma or colorectal cancer. Pregnancy zone protein (PZP) is an antiprotease-resistant immunosuppressant belonging to the α-macroglobulin (αM) protein family. PZP is secreted by the liver and was found to be upregulated in plasma during pregnancy. α-2-macroglobulin (Α2M) shares 71 % serial homology with PZP, but low PZP levels do not lead to increased A2M levels in pregnancy. PZP can interact with several factors such as low-density lipoprotein receptor-associated protein (LRP), transforming growth factor-β (TGF-β), 78 kDa glucose-regulated protein (GRP78), and glycoside A (GdA). PZP is involved in the development of glycolipid metabolism disorders, bronchiectasis, Alzheimer's disease (AD), rheumatoid arthritis (RA), myocardial infarction (MI) and inflammatory bowel disease (IBD). PZP is also associated with the progression of tumorigenesis such as breast cancer (BC), homologyepatocellular carcinoma (HCC), lung adenocarcinoma (LAC), and colorectal cancer (CRC). Therefore, this review analyzes the role of PZP in pathophysiology of various diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Alzheimer's disease (AD) can be effectively managed when detected early. • Deep learning models have the potential to classify the stages of AD from brain MRI. • ViTAD performed excellently over deep learning models on AD classification. • ViTAD has the potential for clinical use in early AD detection and classification. Alzheimer's disease (AD) is a progressive neurological disorder that significantly impairs cognitive functions, particularly memory and thinking skills. The presence of AD in millions of individuals worldwide constitutes a substantial global health challenge. Timely and accurate diagnosis of AD is critical for effective management and improved patient outcomes. This study introduces ViTAD, an innovative method for classifying five stages of AD from brain MRI images, leveraging a Vision Transformer (ViT) model. The proposed model modifies Google's ViT architecture, incorporating fine-tuned hyperparameters and additional layers to enhance its performance for AD stage detection. The dataset comprises 1,296 brain MRI images from the ADNI dataset, covering five stages of AD: Cognitively Normal (CN), Early Mild Cognitive Impairment (EMCI), Late Mild Cognitive Impairment (LMCI), Mild Cognitive Impairment (MCI), and Alzheimer's Disease (AD). Our preprocessing pipeline includes grayscale to RGB conversion, image cropping, and the application of a Laplacian sharpening filter to enhance image clarity. Data augmentation was performed using horizontal/vertical flips, zoom, and rotation to ensure model robustness. We allocated 85% of the dataset for training and 15% for testing. Upon training the model for 20 epochs with a learning rate of 0.0001, ViTAD achieved a remarkable 99.98% accuracy, with 100% precision and an F1-score of 1.00. ViTAD's superior performance in the multi-class classification task outperforms several conventional CNN-based models such as DenseNet and EfficientNet, which struggled with the 5-class AD detection task. Additionally, ViTAD demonstrated high efficiency, achieving optimal accuracy within only 8 epochs, far surpassing traditional CNN models in speed and accuracy. These findings highlight the significant potential of ViTAD as an automated, accurate, and efficient tool for early diagnosis of AD, offering valuable support in clinical settings. [ABSTRACT FROM AUTHOR]

Neurological disorders are the second leading cause of death globally, with Alzheimer's disease (AD) emerging as a significant contributor, responsible for 276 million cases in disability-adjusted life years. Conventional diagnostic methods are often invasive, costly, and place a considerable strain on global healthcare systems. In this study, we presented an innovative and efficient strategy for AD assessment through blood profiling using a multiwell glass chip integrated with aptamer-based surface-enhanced Raman scattering (SERS) biosensors. High-affinity aptamers were selected using capillary electrophoresis-based systematic evolution of ligands by exponential enrichment (CE-SELEX). A mouse brain injury model was employed to systematically investigate biomarkers indicative of physiological, vascular, and cellular damage, such as neurogranin (Nrgn), angiopoietin-2 (Angio-2), PRDX3, lactate dehydrogenase (L-LDH), and τ-441, which were quantified at atto-molar levels in blood samples. Additionally, with the aid of CT-scan imaging, an aptamer-SERS assay was developed to evaluate the dynamic regulation of AD biomarkers. The aptamer-SERS biosensor system was also applied to human samples, demonstrating its capability to multiplex AD biomarkers and establish a time-dependent correlation between percentage biomarker regulation and disease progression. The innovative design, fabrication of aptamer-SERS nanoprobes, and the bio-sensing outcomes illustrate the strong potential of this approach for selective, sensitive, and quantitative early-stage AD diagnosis in clinical applications. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) species (Aβ fibrils and Aβ plaques), as one of the typical pathological markers of Alzheimer's disease (AD), plays a crucial role in AD diagnosis. Currently, some near-infrared I (NIR I) Aβ probes have been reported in AD diagnosis. However, they still face challenges such as strong background interference and the lack of effective probe design. In this study, we propose molecular design strategy that incorporates CN group and amphiphilic modulation to synthesize a series of amphiphilic NIR I Aβ probes, surpassing the commercial probe ThT and ThS. Theoretical calculations indicate that these probes exhibit stronger interaction with amino acid residues in the cavities of Aβ. Notably, the probes containing CN group display the ability of binding two distinct sites of Aβ, which dramatically enhanced the affinity to Aβ species. Furthermore, these probes exhibit minimal fluorescence in aqueous solution and offer ultra-high signal-to-noise ratio (SNR) for in vitro labeling, even in wash-free samples. Finally, the optimal probe DM-V2CN-PYC3 was utilized for in vivo imaging of AD mice, demonstrating its rapid penetration through the blood-brain barrier and labelling to Aβ species. Moreover, it enabled long-term monitoring for a duration of 120 min. These results highlight the enhanced affinity and superior performance of the designed NIR I Aβ probe for AD diagnosis. The molecular design strategy of CN and amphiphilic modulation presents a promising avenue for the development Aβ probes with low background in vivo / in vitro imaging for Aβ species. Tailoring high-performance Aβ Probes based on CN and amphipathic regulatory strategies. [Display omitted] • The high performance NIR Aβ probes are constructed by molecular design strategies. • These NIR Aβ probes exhibit significantly higher affinity to Aβ fibrils than commercial ThT. • The AD brain slices stained with the probes are imaged with ultra-high signal-to-noise ratio (SNR) even without washing. • DM-V2CN-PYC3 can label Aβ deposits in vivo imaging of AD mice with low background. [ABSTRACT FROM AUTHOR]

The Frontal Assessment Battery (FAB) is widely used to assess executive dysfunction in patients with amnestic mild cognitive impairments due to Alzheimer's disease (aMCI-AD), but its neurobiological meaning is unclear. To elucidate this, we examined the relationship between the FAB score and three key imaging biomarkers: gray matter volume, amyloid-beta (Aβ) deposition, and glucose metabolism. Twenty Aβ- and tau-positive aMCI-AD patients and age-matched controls underwent structural magnetic resonance imaging and positron emission tomography with [11C]PiB and [18F]FDG. Voxel-based morphometry and statistical parametric mapping analyses were performed to elucidate the relationships between FAB scores and regional gray matter volume, [11C]PiB uptake for Aβ deposition, and [18F]FDG uptake for glucose metabolism. FAB scores were significantly lower in aMCI-AD than in controls (p < 0.001). In aMCI-AD, FAB was significantly correlated with right inferior frontal gray matter volume and right medial and left middle frontal glucose metabolism (family-wise error p < 0.05). However, there was no correlation between Aβ deposition and FAB (family-wise error p < 0.05). The decreased FAB score is linked more with frontal-lobe neurodegeneration than with Aβ pathology in aMCI-AD. The FAB could be an early marker for neurodegeneration related to frontal-lobe executive dysfunction. • aMCI due to AD patients showed frontal cognitive impairments detected by FAB. • FAB scores were independent of memory and visuospatial dysfunction. • FAB in aMCI due to AD was associated with the inferior frontal gyrus atrophy. • FAB was associated with glucose hypometabolism in the medial and middle frontal gyrus. • There was no correlation between FAB and Aβ deposition. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is the most common form of dementia among elderly people. This disease imposes a significant burden on the healthcare system, society, and economy due to the increasing global aging population. Current trials with drugs or bioactive compounds aimed at reducing cerebral Amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles, which are the two main hallmarks of this devastating neurodegenerative disease, have not provided significant results in terms of their neuropathological outcomes nor met the expected clinical end-points. Ageing, genetic and environmental risk factors, along with different clinical symptoms suggest that AD is a complex and heterogeneous disorder with multiple interconnected pathological pathways rather than a single disease entity. In the present review, we highlight and discuss various non-canonical, Aβ-independent mechanisms, like gliosis, unhealthy dietary intake, lipid and sugar signaling, and cerebrovascular damage that contribute to the onset and development of AD. We emphasize that challenging the traditional "amyloid cascade hypothesis" may improve our understanding of this age-related complex syndrome and help fight the progressive cognitive decline in AD. [Display omitted] • Aging is the major risk factor for the development of Alzheimer's Disease (AD). • AD is a complex and heterogeneous disorder with multiple pathogenic pathways. • Gliosis, unhealthy diet, and vascular injury trigger amyloid and tau accumulation. • Highlighted innovative therapeutic approaches for clinical management of AD. [ABSTRACT FROM AUTHOR]

Elevated levels of butyrylcholinesterase (BuChE) have the potential to be predictive in the timely detection and diagnosis of Alzheimer's disease (AD). By inhibiting of BuChE activity can raise acetylcholine levels and intervene AD processes. Therefore, BuChE as an important factor in treatment AD has been given more and more attention in clinical studies. Given the facts above, in this study, for precise monitoring of BuChE level changes and screening for possible butyrylcholinesterase inhibitor (BuChEI) for AD diagnosis and therapy, a near-infrared (NIR) fluorescence probe (NFP-BuChE) was created. The probe exhibits excellent sensitivity and selectivity for BuChE. NFP-BuChE has been successfully applied to the detection of endogenous BuChE levels in live cells, and we successfully constructed a screening system for BuChEI on cells and a novel natural efficient BuChEI (matrine) was discovered and identified, which significantly reduced BuChE activity and thus alleviated AD symptoms. Most importantly, for the first time, we measured the changes of BuChE levels in zebrafish (0–4 days) after fertilization, various organs of zebrafish, and AD zebrafish modeled by different concentrations of AlCl 3 by NFP-BuChE , and at the same time, we also validated the inhibitory effect of matrine on BuChE by NFP-BuChE in zebrafish. In addition, NFP-BuChE has also been successfully used to measure the changes of BuChE levels in the brains of AD mice. These findings imply that NFP-BuChE is a potentially useful molecular tool for screening possible natural BuChEI quickly and for monitoring changes in BuChE activity, and it is expected that more value will be explored in mice. In addition, matrine and its derivatives are promising options for future Alzheimer's disease treatments. [Display omitted] • A novel near-infrared fluorescence probe NFP-BuChE for detecting BuChE activity. • The probe NFP-BuChE was used for constructing a screening system for BuChEI. • We first determined matrine with good BuChE inhibitory effect in zebrafish. • The probe NFP-BuChE was utilized to image BuChE in various organs of zebrafish. [ABSTRACT FROM AUTHOR]

[Display omitted] • This review highlights hypotheses like amyloid plaque formation, helping in understanding the main cause of AD progression. • Amyloid plaque and neurofibrillary tangles (NFT) are characteristic of Alzheimer's disease (AD). • Dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A) involved in the generation of amyloid plaque and NFT. • This review summarizes the development and optimization of selective DYRK1A inhibitors targeting neurodegenerative diseases. • SAR and optimization of DYRK1A inhibitors offer insights for developing novel, selective, and potent DYRK1A inhibitors. Alzheimer's disease (AD) is a complex disorder that is influenced by a number of variables, such as age, gender, environmental factors, disease, lifestyle, infections, and many more. The main characteristic of AD is the formation of amyloid plaque and neurofibrillary tangles (NFT), which are caused by various reasons such as inflammation, impairment of neurotransmitters, hyperphosphorylation of tau protein, generation of toxic amyloid beta (Aβ) 40/42, oxidative stress, etc. Protein kinases located in chromosome 21, namely dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A), play an essential role in the pathogenesis of AD. DYRK1A stimulates the Aβ peptide aggregation and phosphorylation of tau protein to generate the NFT formation that causes neurodegeneration. Thus, DYRK1A is associated with AD, and inhibition of DYRK1A has the potential to treat AD. In this review, we discussed the pathophysiology of AD, various factors responsible for AD, and the role of DYRK1A in AD. We have also discussed the latest therapeutic potential of DYRK1A inhibitors for neurogenerative disease, along with their structure–activity relationship (SAR) studies. This article provides valuable information for guiding the future discovery of novel and target-specific DYRK1A inhibitors over other kinases and their structural optimization to treat AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent type of dementia of the nervous system that causes many brain functions to weaken (eg, memory loss). Non-invasive early diagnosis of AD has attracted a lot of research attention nowadays as early diagnosis is the most important factor in improving patient care and treatment results. This research develops a deep learning-based pipeline for accurate diagnosis and stratification of AD stages. The proposed analysis pipeline utilizes shallow Convolutional Neural Network (CNN) architecture and 2D T1-weighted Magnetic Resonance (MR) brain images. The proposed pipeline not only introduces a fast and accurate AD diagnosis module but also provides a global classification (i.e., normal vs. Mild Cognitive Impairment (MCI) vs. AD) as well as local classification. The latter deals with an even more challenging task to stratify MCI into a Very Mild Dementia (VMD), mild dementia (MD), and Moderate Dementia (MoD) as the prodromal AD stage. In addition, we compare our approach to cutting-edge deep learning architectures, e.g., DenseNet121, ResNet50, VGG 16, EfficientNetB7, and InceptionV3. The reported results documented the high accuracy and the suggested method's resilience, as evidenced by the overall testing accuracy of 99.68%. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD. [Display omitted] • A decline in brain glucose levels and metabolism is pathologically linked to AD and dementia. • Insulin resistance and mitochondrial dysfunction are implicated in classic plaque and tangle pathologies of AD. • Aberrant IRS/PI3K/Akt/AMPK signaling and abnormal GLUT activities are directly linked to the etiology of neurodegeneration. • Defective glucose metabolism-induced polyol activation, AGEs accumulation and oxidative stress contribute to AD pathogenesis. • Abnormal glucose metabolism endorses cerebral autophagy/mitophagy dysregulation by hampering lysosome-mitochondrial functions. [ABSTRACT FROM AUTHOR]

Classification of Alzheimer's disease (AD) is one of the most challenging issues for neurologists. Manual methods are time consuming and may not be accurate all the time. Since, brain is the most affected region in AD, a proper classification framework using brain images may provide more accurate results. Deep Learning (DL) is a popular representation of machine learning techniques, that emulate the functionalities of a human brain to process information and creates patterns that help in making complex decisions. The ability to absorb information, even from the unstructured and unlabeled data, makes DL one of the first choices by researchers. In this paper, some of the most popular DL models are discussed along with their implementation results for AD classification. All brain Magnetic Resonance (MR) images are acquired from the online data-set, "Alzheimer's Disease Neuroimaging Initiative (ADNI)". From the performance comparison amongst all the discussed models, it is observed that the DenseNet-121 model achieves a convincing result with an average performance rate of 88.78%. But one limitation of the DenseNet model is that it uses lots of convolutional operations that make the model computationally slower than many of the discussed models. Depth-wise convolution is a popular way to make a convolutional operation faster and better. Hence, to improve the execution time, we have proposed replacing the convolution layers in the original DenseNet-121 architecture with depth-wise convolution layers. The new architecture also improved the performance of the model with an average rate of 90.22%. [ABSTRACT FROM AUTHOR]

β-amyloid (Aβ) 25–35 peptide-induced oxidative stress is one of the primary reasons for the development of Alzheimer's disease (AD). In the present study, α-bisabolol β- D -fucopyranoside (ABFP) was evaluated for its protective effect against β-amyloid (Aβ) 25–35 peptide-induced toxicity in Neuro-2a cells. The results of the current study revealed that ABFP inhibits acetylcholinesterase, apart from reducing the formation of lipid peroxides, protein carbonyls, and nitric oxides in Neuro-2a cells during the treatment of β-amyloid (Aβ) 25–35 peptide. Additionally, ABFP effectively prevented the mitochondrial membrane damage induced by the β-amyloid (Aβ) 25–35 peptide in Neuro-2a cells. Furthermore, ABFP was found to significantly inhibit caspase 3 production in Neuro-2a cells, which was confirmed through AO/EtBr, Annexin-V/FITC, and PI fluorescent microscopic images, indicating that ABFP has anti-apoptotic properties. In addition, ABFP also increased the anti-apoptotic protein expression and protected the Neuro-2a cell from β-amyloid (Aβ) 25–35 peptide-induced toxicity. The in silico molecular docking analysis of ABFP with GSK-3beta showed that it was able to bind with Asn 186, Asp 200, and Lys 183 residues of the enzyme. Overall, the results suggest that ABFP acts as a potent drug against oxidative stress-mediated cell death in AD. [Display omitted] • α-bisabolol β- D -fucopyranoside was found to exhibit Anti-cholinesterase, Anti-oxidant, and Anti-apoptotic property. • It formed a stable complex with Glycogen synthase kinase-3β when compared to Tau and N-methyl D-aspartate receptors. • Overall, ABFP acts as a potential lead against β-amyloid peptide and it can be suggested for the treatment of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

• Sulforaphane (Sfn) is a antioxidant and anti-inflammatory compound naturally found in cruciferous vegetables. • Alzheimer's disease (AD) and vascular cognitive impairment (VCI) are the major causes of dementia. • Sulforaphane (Sfn) improves cognitive functions and decreases Aβ and p-tau levels in VCI rats, indicating its potential as a therapeutic agent for treating VCI and AD. • The protective mechanisms of Sfn involve the induction of HO-1 expression, activation of the Akt/GSK3β pathway, and modulation of amyloid precursor protein (APP) expression levels. Sulforaphane (Sfn) is a compound naturally found in cruciferous vegetables such as broccoli, Brussels sprouts, cabbage, and kale. It is well-known for its antioxidative and anti-inflammatory effects. Sfn has attracted attention for its potential health benefits, particularly its role in brain health and the potential prevention of dementia and neurodegeneration. Alzheimer's disease (AD) and vascular cognitive impairment (VCI) are the top two causes of dementia. Cerebral vascular lesions give rise to VCI and predispose neurons to degeneration and Alzheimer's disease (AD) by Aβ accumulation and tau hyperphosphorylation. In a rat model of VCI by permanent bilateral common carotid artery occlusion (2VO), we tested the protective effect of the phase II enzyme inducer sulforaphane (Sfn). Sfn ameliorates vascular cognitive deficits by reducing the typical white matter injury and neural atrophy pathological changes in VCI. Moreover, for the first time, we demonstrated that it effectively reduced Aβ and toxic p-tau accumulation in VCI. The protective mechanisms of Sfn involve the induction of HO-1 expression, activation of the Akt/GSK3β pathway, and modulation of amyloid precursor protein (APP) expression levels. Our data suggest that Sfn is a promising therapeutic compound to treat VCI and AD. It inhibits short-term neuron and white matter injuries as well as long-term Aβ and p-tau accumulation caused by cerebral vascular lesions. [Display omitted] [ABSTRACT FROM AUTHOR]

• Investigated use of deep learning and EEG signals for AD and MCI. • Applied PRISMA to search PubMed/WOS/IEEE/Scopus databases. • Selected 74 studies published between 2013 and 2024. • CNN model for AD, ResNet for MCI was found effective. • Limitations and future challenges are presented. Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) are progressive neurological disorders that significantly impair the cognitive functions, memory, and daily activities. They affect millions of individuals worldwide, posing a significant challenge for its diagnosis and management, leading to detrimental impacts on patients' quality of lives and increased burden on caregivers. Hence, early detection of MCI and AD is crucial for timely intervention and effective disease management. This study presents a comprehensive systematic review focusing on the applications of deep learning in detecting MCI and AD using electroencephalogram (EEG) signals. Through a rigorous literature screening process based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the research has investigated 74 different papers in detail to analyze the different approaches used to detect MCI and AD neurological disorders. The findings of this study stand out as the first to deal with the classification of dual MCI and AD (MCI+AD) using EEG signals. This unique approach has enabled us to highlight the state-of-the-art high-performing models, specifically focusing on deep learning while examining their strengths and limitations in detecting the MCI, AD, and the MCI+AD comorbidity situations. The present study has not only identified the current limitations in deep learning area for MCI and AD detection but also proposes specific future directions to address these neurological disorders by implement best practice deep learning approaches. Our main goal is to offer insights as references for future research encouraging the development of deep learning techniques in early detection and diagnosis of MCI and AD neurological disorders. By recommending the most effective deep learning tools, we have also provided a benchmark for future research, with clear implications for the practical use of these techniques in healthcare. [ABSTRACT FROM AUTHOR]

• The LIMMA and WGCNA significantly improved the discrimination ability of AD targets. • The LASSO and five CytoHubba algorithms were combined to obtain AD hub genes. • The combination of molecular docking and MD simulation. • Prove the feasibility of EBHM regulation of ferroptosis for treating AD. Ferroptosis plays a role in Alzheimer's disease (AD) development. Erigeron breviscapus (Vant.) Hand-Mazz (EBHM) shows promising effects in treating cognitive impairment-related diseases. However, the mechanisms by which EBHM regulates ferroptosis in AD treatment are not fully understood. This study used bioinformatics, network pharmacology, molecular docking, and molecular dynamics simulation to explore how EBHM regulates ferroptosis in AD treatment. The results identified four key genes—HSPA8, GSK3B, CTSB, and YWHAG—that are involved in this regulation, and constructed a multigene diagnostic model for AD. The model demonstrated moderate accuracy (area under the curve [AUC] = 0.636) in distinguishing AD from non-demented (ND) and was further validated with external datasets showing good diagnostic capabilities (AUC values of 0.898, 0.889, 0.746, and 0.712). Additionally, CIBERSORT analysis revealed a significant correlation between immune cell infiltration and these four genes, highlighting their potential role in AD immunity. Molecular docking studies indicated that 3,4,5-tricaffeoylquinic acid (TCQA) had the highest binding affinity to HSPA8, suggesting that TCQA and HSPA8 are key components and core targets in EBHM's regulation of ferroptosis in AD therapy. Molecular dynamics simulations confirmed the stability and strong binding affinity of the TCQA-HSPA8 complex. These findings enhance our understanding of the molecular mechanisms underlying ferroptosis regulation by EBHM for the treatment of AD and may offer new avenues for developing effective AD treatments. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a degenerative brain disease that affects millions of people worldwide. It is caused by abnormalities in cholinergic neurons, oxidative stress, and inflammatory cascades. The illness is accompanied by personality changes, memory issues, and dementia. Metabolic signaling pathways help with fundamental processes like DNA replication and RNA transcription. Being adaptable is essential for both surviving and treating illness. The body's metabolic signaling depends on adipokines, including adiponectin (APN) and other adipokines secreted by adipose tissues. Energy homeostasis is balanced by adipokines, and nutrients. Overconsumption of nutrients messes with irregular signaling of adipokines, such as APN in both peripheral and brain which leads to neurodegeneration, such as AD. Despite the failure of traditional treatments like memantine and cholinesterase inhibitors, natural plant bioactive substances like Osmotin (OSM) have been given a focus as potential therapeutics due to their antioxidant properties, better blood brain barrier (BBB) permeability, excellent cell viability, and especially nanoparticle approaches. The review highlights the published preclinical literature regarding the role of OSM in AD pathology while there is a need for more research to investigate the hidden therapeutic potential of OSM which may open a new gateway and further strengthen its healing role in the pathogenesis of neurodegeneration, especially AD. • Metabolic homeostasis plays an important role in Periphery and CNS. • Adiponectin (APN) metabolic signaling is crucial for homeostatic balance in Periphery and CNS. • Alzheimer's Disease (AD) is closely related to metabolic abnormalities. • APN plays a leading role in metabolic syndrome (MetS) and AD Pathogenesis. • Osmotin is an emerging therapeutic approach for AD pathology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), marked by tau tangles and amyloid-beta plaques, leads to cognitive decline. Despite extensive research, its complex etiology remains elusive, necessitating new treatments. This study utilized machine learning (ML) to analyze compounds with neuroprotective potential. This approach exposed the disease's complexity and identified important proteins, namely MTOR and BCL2, as central to the pathogenic network of AD. MTOR regulates neuronal autophagy and survival, whereas BCL2 regulates apoptosis, both of which are disrupted in AD. The identified compounds, including Armepavine, Oprea1_264702,1-cyclopropyl-7-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid,(2S)-4′-Hydroxy-5,7,3′-trimethoxyflavan,Oprea1_130514,Sativanone,5-hydroxy-7,8-dimethoxyflavanone,7,4′-Dihydroxy-8,3′-dimethoxyflavanone,N,1-dicyclopropyl-6,Difluoro-Methoxy-Gatifloxacin,6,8-difluoro-1-(2-fluoroethyl),1-ethyl-6-fluoro-7-(4-methylpiperidin-1-yl),Avicenol C, demonstrated potential modulatory effects on these proteins. The potential for synergistic effects of these drugs in treating AD has been revealed via network pharmacology. By targeting numerous proteins at once, these chemicals may provide a more comprehensive therapeutic approach, addressing many aspects of AD's complex pathophysiology. A Molecular docking, dynamic simulation, and Principle Component Analysis have confirmed these drugs' efficacy by establishing substantial binding affinities and interactions with important proteins such as MTOR and BCL2. This evidence implies that various compounds may interact within the AD pathological framework, providing a sophisticated and multifaceted therapy strategy. In conclusion, our study establishes a solid foundation for the use of these drugs in AD therapy. Thus current study highlights the possibility of multi-targeted, synergistic therapeutic approaches in addressing the complex pathophysiology of AD by integrating machine learning, network pharmacology, and molecular docking simulations. This holistic technique not only advances drug development but also opens up new avenues for developing more effective treatments for this difficult and widespread disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a prevalent neurodegenerative condition affecting a substantial portion of the global population. It is marked by a complex interplay of factors, including the accumulation of amyloid plaques and tau tangles within the brain, leading to neuroinflammation and neuronal damage. Recent studies have underscored the role of free lipids and their derivatives in the initiation and progression of AD. Eicosanoids, metabolites of polyunsaturated fatty acids like arachidonic acid (AA), emerge as key players in this scenario. Remarkably, eicosanoids can either promote or inhibit the development of AD, and this multifaceted role is determined by how eicosanoid signaling influences the immune responses within the brain. However, the precise molecular mechanisms dictating the dual role of eicosanoids in AD remain elusive. In this comprehensive review, we explore the intricate involvement of eicosanoids in neuronal function and dysfunction. Furthermore, we assess the therapeutic potential of targeting eicosanoid signaling pathways as a viable strategy for mitigating or halting the progression of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aβ deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements. • Role of G6PD (glucose-6-phosphate dehydrogenase) in Alzheimer's Disease. • Therapeutic approaches of G6PD in Alzheimer's Disease. • Advancement of Microfluidic approaches for G6PD in Alzheimer's Disease. • Enhancement of G6PD in the brain through Nanoparticle Approaches: a potential treatment of Alzheimer's Disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder initiated by amyloid-beta (Aβ) accumulation, leading to impaired cognitive function. Several delivery approaches have been improved for AD management. Among them, human serum albumin (HSA) is broadly employed for drug delivery and targeting the Aβ in AD owing to its biocompatibility, Aβ inhibitory effect, and nanoform, which showed blood-brain barrier (BBB) crossing ability via glycoprotein 60 (gp60) receptor and secreted protein acidic and rich in cysteine (SPARC) protein to transfer the drug molecules in the brain. Thus far, there is no previous review focusing on HSA and its drug delivery system in AD. Hence, the reviewed article aimed to critically compile the HSA therapeutic as well as drug delivery role in AD management. It also delivers information on how HSA-incorporated nanoparticles with surfaced embedded ligands such as TAT, GM1, and so on, not only improve BBB permeability but also increase neuron cell targetability in AD brain. Additionally, Aβ and tau pathology, including various metabolic markers likely BACE1 and BACE2, etc., are discussed. Besides, the molecular interaction of HSA with Aβ and its distinctive forms are critically reviewed that HSA can segregate Zn(II) and Cu(II) metal ions from Aβ owing to high affinity. Furthermore, the BBB drug delivery challenges in AD are addressed. Finally, the clinical formulation of HSA for the management of AD is critically discussed on how the HSA inhibits Aβ oligomer and fibril, while glycated HSA participates in amyloid plaque formation, i.e., β-structure sheet formation. This review report provides theoretical background on HSA-based AD drug delivery and makes suggestions for future prospect-related work. [Display omitted] • This review provides insight into Alzheimer's disease and discusses its pathology with metabolic marks. • This review describes the potential role of HSA in Aβ-binding and aggregation–inhibiting effects. • Discussing the role of various HSA-modified forms and challenges for BBB drug permeability. • This review summarizes HSA-based drug delivery applications for AD treatment. • Comprehensively discuss the HSA-based clinical formulation with a future prospective. [ABSTRACT FROM AUTHOR]

Emerging as a promising drug target for Alzheimer's disease (AD) therapy, glycogen synthase kinase 3β (GSK-3β) has garnered attention. This study sought to rigorously scrutinize a compendium of natural compounds retrieved from the ZINC database through pharmacodynamic experiments, employing a 1 H-indazole-3-carboxamide (INDZ) scaffold, to identify compounds capable of inhibiting the GSK-3β protein. Utilizing a multi-step approach, the study involved pharmacophore analysis, followed by molecular docking to select five promising ligands for further investigation. Subsequently, ESMACS simulations were employed to assess the stability of the ligand-protein interactions. Evaluation of the binding modes and free energy of the ligands revealed that five compounds (2a-6a) exhibited crucial interactions with the active site residues. Furthermore, various methodologies, including hydrogen bond and clustering analyses, were utilized to ascertain their inhibitory potential and elucidate the factors contributing to ligand binding in the protein's active site. The findings from MMPBSA/GBSA analysis indicated that these five selected small molecules closely approached the IC50 value of the reference ligand (OH8), yielding energy values of −34.85, −32.58, −31.71, and −30.39 kcal/mol, respectively. Additionally, an assessment of the interactions using hydrogen bond and dynamic analyses delineated the effective binding of the ligands with the binding pockets in the protein. Through computational analysis, we obtained valuable insights into the molecular mechanisms of GSK-3β, aiding in the development of more potent inhibitors. [Display omitted] • We used molecular docking and dynamics to find natural compounds inhibiting gsk-3β, a target for Alzheimer's therapy. • Utilized a multi-step computational approach, including pharmacophore analysis, docking, and ESMACS simulations, to assess ligands. • Identified five compounds with significant inhibitory potential against gsk-3β, based on binding modes and free energy. • Provided insights into gsk-3β inhibition mechanisms through hydrogen bond and clustering analyses of ligand-protein interactions. • Highlighted five small molecules as promising therapeutic candidates for Alzheimer's, with IC50 values close to the reference ligand. [ABSTRACT FROM AUTHOR]

• Nold, ADD and DLB subjects show a reduction in the posterior rsEEG alpha activities at the eyes-opening. • Compared to Nold, ADD and DLB subjects show less reactivity of the posterior alpha source. • Compared to ADD, DLB subjects show less reactivity of the posterior alpha source. Please modify the Abstract as follows:Here we tested if the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms from the eye-closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer's disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems.We used clinical, demographical, and rsEEG datasets in 28 older adults (Healthy), 42 DLB, and 48 ADD participants. The eLORETA freeware was used to estimate cortical rsEEG sources.Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. That reduction in the occipital region was lower in the DLB than in the ADD group.These results suggest that DLB patients may suffer from a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. [ABSTRACT FROM AUTHOR]

• In CN, WMH associates with frontotemporal cortical thickness independent of regional Aβ. • In MCI, WMH associates with temporal and cingulate thickness independent of regional Aβ. • In MCI, temporal Aβ associates with temporal cortical thickness independent of WMH. • No interactions of WMH with regional Aβ on regional cortical thickness were found. • WMH, composite regional Aβ and cortical thickness independently predicted progression to dementia. White matter hyperintensities (WMH) and β-amyloid (Aβ) accumulation have both been linked to neurodegeneration in Alzheimer's disease (AD). However, the independent effects of global WMH and regional Aβ on the corresponding regional cortical thickness have not been investigated. Here, we evaluated 280 cognitively normal (CN), 450 mild cognitive impairment (MCI), and 63 individuals with AD dementia separately. In CN individuals, only WMH was associated with lower cortical thickness in fronto-temporal regions, independent of regional Aβ deposition in the corresponding cortical regions. In MCI individuals, the spatial pattern of independent WMH associations was predominantly in temporal and cingulate regions, while independent regional Aβ associations were now evident in temporal regions. No regional interactions were found. In non-demented individuals and MCI individuals alone, we found that global WMH, composite regional Aβ burden and cortical thickness in AD-associated regions all independently predicted progression to AD dementia. Our findings suggest that the independent effects of global WMH and regional Aβ on regional cortical thickness are spatially different, converging in temporal regions in MCI individuals. [ABSTRACT FROM AUTHOR]

• Segmentation methods HIPS, volBrain and CAT were used successfully in the classification of HC, AD and MCI. • Segmentation method BrainSuite did not conform with the other three methods. • ADNI (n = 138) data was split into AD, mild cognitive impairment (MCI) and HC. Automated segmentation methods are developed to help with the segmentation of different brain areas. However, their reliability has yet to be fully investigated. To have a more comprehensive understanding of the distribution of changes in Alzheimer's disease (AD), as well as investigating the reliability of different segmentation methods, in this study we compared volumes of cortical and subcortical brain segments, using HIPS, volBrain, CAT and BrainSuite automated segmentation methods between AD, mild cognitive impairment (MCI) and healthy controls (HC). A total of 182 MRI images were taken from the minimal interval resonance imaging in Alzheimer's disease (MIRIAD; 22 AD and 22 HC) and the Alzheimer's disease neuroimaging initiative database (ADNI; 43 AD, 50 MCI and 45 HC) datasets. Statistical methods were used to compare different groups as well as the correlation between different methods. The two methods of volBrain and CAT showed a strong correlation (p's < 0.035 Bonferroni corrected for multiple comparisons). The two methods, however, showed no significant correlation with BrainSuite (p 's > 0.820 Bonferroni corrected). Furthermore, BrainSuite did not follow the same trend as the other three methods and only HIPS, volBrain and CAT showed strong conformity with the past literature with strong correlation with mini mental state examination (MMSE) scores. Our results showed that automated segmentation methods HIPS, volBrain and CAT can be used in the classification of HC, AD and MCI. This is an indication that such methods can be used to inform researchers and clinicians of underlying mechanisms and progression of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies. Celastrol is a novel TFEB activator that promotes degradation of phosphorylated Tau aggregates and improves memory deficiency in AD animal models via activating TFEB-mediated autophagy. [Display omitted] [ABSTRACT FROM AUTHOR]

• Single cell based analyses promote greater understanding of Alzheimer's disease. • Mitochondrial function and energy production are implicated in a mouse model. • Mouse Apoe is involved in the generation of specific polyadenylated transcripts. • Single cell studies could inform treatments that target specific brain cell types. A dataset of single-nucleus RNA sequencing (snRNAseq) data was analyzed using Seurat, Sierra, and Ingenuity Pathway Analysis (IPA) programs to assess differentially expressed genes (DEGs) and differential transcript usage (DTU) in mouse hippocampal cell types. Seurat identified DEGs between the wild type (WT) and Apoe knockout (EKO) mice. IPA identified 11 statistically significant canonical pathways in >1 cell type. Sierra identified Sipa1l1 with DTU between WT and EKO samples. Analysis of the Sipa1l1 peak region identified an alternative non-canonical polyadenylation signal and a putative cytoplasmic polyadenylation element. APOE regulation of gene transcription and co-transcriptional RNA processing may underlie Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Hyperglycemia leads to lipid peroxidation, producing 4‐hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aβ), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aβ, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD. A total of 239 Taiwanese serum samples from a healthy control group and patients with hyperglycemia, and AD with and without hyperglycemia were analyzed. Aβ was immunoprecipitated from randomly pooled serum in each group and immunoblotted. Synthetic Aβ 1-16 and Aβ 17-28 peptides were modified with HNE in vitro and verified with LC-MS/MS. The levels of Aβ, HNE adducts, and autoantibody isotypes IgG and IgM against either native or HNE-modified Aβ were determined with ELISA. The diagnostic power of potential biomarkers was evaluated. Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aβ, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aβ were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aβ for both hyperglycemia and AD. Additionally, HNE-Aβ peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD. Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (A β) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy–lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy–lysosomal pathway in AD. We then describe the interplay between the autophagy–lysosomal pathway and two pathological proteins, A β and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy–lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy–lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy–lysosomal pathway for AD treatment. Multiple factors including gene mutations impair autophagy–lysosomal pathway, and exaggerate AD progression. Enhancing autophagy can reduce A β levels, promote pathological tau degradation and thus is a promising therapeutic strategy for Alzheimer's disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD.Design, Setting, and Participants: This hospital-based prospective longitudinal study enrolled 109 patients with AD. All patients with AD were evaluated at 3-month intervals to investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD.Outcome Measure: The main outcome measure was time-to-progression from AD to incident psychosis. The thickness or volume of medial temporal lobe structures (i.e., the hippocampus, entorhinal cortex, and parahippocampus) were measured using magnetic resonance imaging and the Freesurfer automated segmentation pipeline at baseline.Results: Multivariate Cox proportional hazards regression analysis revealed that a decreased cortical thickness or volume of medial temporal region was associated with a higher risk of incident psychosis in patients with AD. The hazard ratios for decreased cortical thickness of the left entorhinal cortex and decreased cortical volume of the right hippocampus were 4.291 (95% confidence interval [CI], 1.196-15.384) and 2.680 [(CI, 1.003-1.196]), respectively.Conclusion: Our study revealed that decreased cortical thickness or volume of medial temporal sub-regions is a risk factor for incident psychosis in patients with AD. A careful assessment of the thickness or volume of the medial temporal lobe structures in AD may improve early detection and intervention of psychosis in AD. [ABSTRACT FROM AUTHOR]

Electroencephalographic (EEG) alpha oscillations have been related to heart rate variability (HRV) and both change in Alzheimer's disease (AD). We explored if task switching reveals altered alpha power and HRV in cognitively healthy individuals with AD pathology in cerebrospinal fluid (CSF) and whether HRV improves the AD pathology classification by alpha power alone. We compared low and high alpha event-related desynchronization (ERD) and HRV parameters during task switch testing between two groups of cognitively healthy participants classified by CSF amyloid/tau ratio: normal (CH-NAT, n = 19) or pathological (CH-PAT, n = 27). For the task switching paradigm, participants were required to name the color or word for each colored word stimulus, with two sequential stimuli per trial. Trials include color (cC) or word (wW) repeats with low load repeating, and word (cW) or color switch (wC) for high load switching. HRV was assessed for RR interval, standard deviation of RR-intervals (SDNN) and root mean squared successive differences (RMSSD) in time domain, and low frequency (LF), high frequency (HF), and LF/HF ratio in frequency domain. Results showed that CH-PATs compared to CH-NATs presented: 1) increased (less negative) low alpha ERD during low load repeat trials and lower word switch cost (low alpha: p = 0.008, Cohen's d = −0.83, 95% confidence interval −1.44 to −0.22, and high alpha: p = 0.019, Cohen's d = −0.73, 95% confidence interval −1.34 to −0.13); 2) decreasing HRV from rest to task, suggesting hyper-activated sympatho-vagal responses. 3) CH-PATs classification by alpha ERD was improved by supplementing HRV signatures, supporting a potentially compromised brain-heart interoceptive regulation in CH-PATs. Further experiments are needed to validate these findings for clinical significance. • Low load task switching challenge revealed increased (less negative) alpha ERD in CH-PATs. • Task switching challenge revealed decreasing HRV from rest to task in CH-PATs. • Supplementing HRV signatures improved binary classification of CH-PATs by alpha ERD alone. [ABSTRACT FROM AUTHOR]

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with β-amyloid (Aβ) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE inhibitor S21 – 1011 (eq BChE IC 50 = 0.059 ± 0.006 μM, h BChE IC 50 = 0.162 ± 0.069 μM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21 – 1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Aβ. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21 – 1011 , a novel potent BChE inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation. [Display omitted] • S21 – 1011 was a potent and selective BChE inhibitor. • S21 – 1011 exhibited satisfactory safety, BBB penetration and PK properties. • S21 – 1011 functioned as a protector against neuroinflammation and oxidative stress. • S21 – 1011 alleviated cognitive impairment in various AD model mice. [ABSTRACT FROM AUTHOR]

Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role in AD by increasing an individual's vulnerability to various infections, which could contribute to neurodegeneration. If true, then vaccines that have heterologous effects on immunity, extending beyond protection against the targeted disease, may hold a potential for AD prevention. We evaluated the associations of common adult infections (herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses), and vaccinations against shingles and pneumonia, with the risks of AD and other dementias in a pseudorandomized sample of the Health and Retirement Study (HRS). Shingles, pneumonia and mycoses, diagnosed between ages 65 and 75, were all associated with significantly increased risk of AD later in life, by 16 %–42 %. Pneumococcal and shingles vaccines administered between ages 65–75 were both associated with a significantly lower risk of AD, by 15 %–21 %. These effects became less pronounced when AD was combined with other dementias. Our findings suggest that both the pneumococcal polysaccharide vaccine and the live attenuated zoster vaccine can offer significant protection against AD. It remains to be determined if non-live shingles vaccine has a similar beneficial effect on AD. This study also found significant associations of various infections with the risk of AD, but not with the risks of other dementias. This indicates that vulnerability to infections may play a more significant role in AD than in other types of dementia, which warrants further investigation. • Shingles, pneumonia, and recurrent mycoses all increased risk of AD after age 75. • Vaccinations against shingles and pneumonia both significantly reduced risk of AD. • The associations with infections and vaccines were stronger for AD than for other dementias. • Results of this study point to a role of compromised immunity in AD. • Pneumococcal and zoster vaccines are promising candidates for repurposing in AD. [ABSTRACT FROM AUTHOR]

• Mitochondria-associated membranes (MAMs) provide a molecular platform for autophagosomes formation. • MAMs positively regulate the mitophagy and autophagy process. • Altered MAMs protein functions associated with impaired autophagic response. • Altered interplay between MAMs proteins and autophagy leads progression of neurodegenerative diseases. Since the discovery of membrane contact sites between ER and mitochondria called mitochondria-associated membranes (MAMs), several pieces of evidence identified their role in the regulation of different cellular processes such as Ca2+ signalling, mitochondrial transport, and dynamics, ER stress, inflammation, glucose homeostasis, and autophagy. The integrity of these membranes was found to be essential for the maintenance of these cellular functions. Accumulating pieces of evidence suggest that MAMs serve as a platform for autophagosome formation. However, the alteration within MAMs structure is associated with the progression of neurodegenerative diseases. Dysregulated autophagy is a hallmark of neurodegeneration. Here, in this review, we highlight the present knowledge on MAMs, their structural composition, and their roles in different cellular functions. We also discuss the association of MAMs proteins with impaired autophagy and their involvement in the progression of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. [ABSTRACT FROM AUTHOR]

• Microbleeds of EFAD are detected by 2 months; most are "naked" with no plaque contact. • Microbleeds and cerebral amyloid angiopathy are distributed in different cortical layers. • The ratio of microbleeds:plaques decreases after 2 months, with female bias. • Microbleed size does not increase with age, suggesting single event of extravasation. • MBs may seed amyloid aggregation in plaque formation. Cerebral microbleeds (MBs) increase at later ages in association with increased cognitive decline and Alzheimer Disease (AD). MB prevalence is also increased by APOE4 and hypertension. In EFAD mice (5XFAD+/−/human APOE+/+), cerebral cortex MBs are most prevalent in E4 females at 6 months, paralleling plaque amyloid. We evaluated MBs at 2, 4, and 6 months in relation to amyloid in plaques and cerebral amyloid angiopathy (CAA) by age, sex, APOE allele, and blood pressure. At 2 mo, MBs were 50% more numerous than plaques, followed by decreased ratio of MBs:Aβ plaques with female excess to 6 mo. The stable size of MBs suggests MBs arise as single events of extravasation, which may "seed" plaque formation. Blood pressure was normal from 2 to 6 months, minimizing a role of hypertension. Memory, assessed by fear conditioning, decreased with age in correlation with MBs and amyloid. Cortical layer analysis showed prevalent MBs and plaque in layers 4 and 5. Contrarily, CAA was prevalent in layers 1 and 2, discounting its contribution to MBs. [ABSTRACT FROM AUTHOR]

• A limited number of respirators may pose an ethical problem for medical nursing staff. • Medical staff were asked to rank respirator allocation to 3 COVID patients. • Respondents were divided between age and cognitive status as the deciding factor. • Determination of a set policy would help professionals with these decisions. The COVID 19 pandemic has led to an increase in the number of patients in need of ventilation. Limitations in the number of respirators may cause an ethical problem for the medical and nursing staff in deciding who should be connected to the available respirators. We conducted a cross-sectional survey among a convenience sample of 278 healthcare professionals at one medical center. They were asked to rank their preference in respirator allocation to three COVID-19 patients, one 80 years old with no cognitive illness, one 50 years old with Alzheimer's disease (AD), and one 80 years old with AD. Most respondents (75%) chose the 80-year-old AD patient as last preference, but were evenly divided on how to rank the other two patients. Medical staff have difficulty deciding whether age or cognitive status should be the deciding factor ventilator allocation. Determination of a set policy would help professionals with these decisions. [ABSTRACT FROM AUTHOR]