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Lactoferrin modification of berberine nanoliposomes enhances the neuroprotective effects in a mouse model of Alzheimers disease.

Previous studies have shown that berberine has neuroprotective effects against Alzheimers disease, including antagonizing tau phosphorylation, and inhibiting acetylcholinesterase activity and neural cell apoptosis. However, its low bioavailability and adverse reactions with conventional administration limit its clinical application. In this study, we prepared berberine nanoliposomes using liposomes characterized by low toxicity, high entrapment efficiency, and biodegradability, and modified them with lactoferrin. Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency. We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimers disease established by injection of amyloid-beta 1-42 into the lateral ventricle. Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus, reduced tau over-phosphorylation in the cerebral cortex, and improved mouse behavior. These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimers disease.

Lamotrigine protects against cognitive deficits, synapse and nerve cell damage, and hallmark neuropathologies in a mouse model of Alzheimers disease.

Lamotrigine (LTG) is a widely used drug for the treatment of epilepsy. Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimers disease. However, the underlying molecular mechanisms remain unclear. In this study, amyloid precursor proteinpresenilin 1 (APPPS1) double transgenic mice were used as a model of Alzheimers disease. Five-month-old APPPS1 mice were intragastrically administered 30 mgkg LTG or vehicle once per day for 3 successive months. The cognitive functions of animals were assessed using Morris water maze. Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay. The cell damage in the brain was investigated using hematoxylin and eosin staining. The levels of amyloid-β and the concentrations of interleukin-1β, interleukin-6 and tumor necrosis factor-α in the brain were measured using enzyme-linked immunosorbent assay. Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction. We found that LTG substantially improved spatial cognitive deficits of APPPS1 mice alleviated damage to synapses and nerve cells in the brain and reduced amyloid-β levels, tau protein hyperphosphorylation, and inflammatory responses. High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimers disease-related neuropathologies may have been mediated by the regulation of Ptgds, Cd74, Map3k1, Fosb, and Spp1 expression in the brain. These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimers disease. Furthermore, these data indicate that LTG may be a promising therapeutic drug for Alzheimers disease.

Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice.

Icariin, a major prenylated flavonoid found in Epimedium spp., is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimers disease. In this study, we investigated the neuroprotective mechanism of icariin in an APPPS1Tau triple-transgenic mouse model of Alzheimers disease. We performed behavioral tests, pathological examination, and western blot assay, and found that memory deficits of the model mice were obviously improved, neuronal and synaptic damage in the cerebral cortex was substantially mitigated, and amyloid-β accumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mgkg body weight per day. Furthermore, deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed, including the insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3-kinase, protein kinase B, and glycogen synthase kinase 3β, and the levels of glucose transporter 1 and 3 were markedly increased. These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimers disease by regulating brain insulin signaling and glucose transporters, which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimers disease.

Crosslink between mutations in mitochondrial genes and brain disorders implications for mitochondrial-targeted therapeutic interventions.

At the present, association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention. Defects in mitochondrial network dynamics, point mutations, deletions, and interaction of pathogenomic proteins with mitochondria are some of the possible underlying mechanisms involved in these neurological disorders. Mitochondrial genetics, defects in mitochondrial oxidative phosphorylation machinery, and reactive oxygen species production might share common crosstalk in the progression of these neurological disorders. It is of significant interests to explore and develop therapeutic strategies aimed at correcting mitochondrial abnormalities. This review provided insights on mitochondrial dysfunctionmutations involved in the progression of Alzheimers disease, Huntingtons disease, and epilepsy with a special focus on Parkinsons disease pathology. Along with the deleterious effects of mitochondrial mutations in aforesaid neurological disorders, this paper unraveled the available therapeutic strategy, specifically aiming to improve mitochondrial dysfunction, drugs targeting mitochondrial proteins, gene therapies aimed at correcting mutant mtDNA, peptide-based approaches, and lipophilic cations.

The neuroprotective effects of oxygen therapy in Alzheimers disease a narrative review.

Alzheimers disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxiaobstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Neurotrophic fragments as therapeutic alternatives to ameliorate brain aging.

Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes. During this physiological process, the brain is the most affected organ due to changes in its structural and chemical functions, such as changes in plasticity and decrease in the number, diameter, length, and branching of dendrites and dendritic spines. Likewise, it presents a great reduction in volume resulting from the contraction of the gray matter. Consequently, aging can affect not only cognitive functions, including learning and memory, but also the quality of life of older people. As a result of the phenomena, various molecules with notable neuroprotective capacity have been proposed, which provide a therapeutic alternative for people under conditions of aging or some neurodegenerative diseases. It is important to indicate that in recent years the use of molecules with neurotrophic activity has shown interesting results when evaluated in in vivo models. This review aims to describe the neurotrophic potential of molecules such as resveratrol (3,5,4-trihydroxystilbene), neurotrophins (brain-derived neurotrophic factor), and neurotrophic-type compounds such as the terminal carboxyl domain of the heavy chain of tetanus toxin, cerebrolysin, neuropeptide-12, and rapamycin. Most of these molecules have been evaluated by our research group. Studies suggest that these molecules exert an important therapeutic potential, restoring brain function in aging conditions or models of neurodegenerative diseases. Hence, our interest is in describing the current scientific evidence that supports the therapeutic potential of these molecules with active neurotrophic.

Extracellular vesicles in Alzheimers disease from pathology to therapeutic approaches.

Alzheimers disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms. Identifying novel biomarkers for Alzheimers disease has the potential for patient risk stratification, early diagnosis, and disease monitoring in response to therapy. A novel class of biomarkers is extracellular vesicles given their sensitivity and specificity to specific diseases. In addition, extracellular vesicles can be used as novel biological therapeutics given their ability to efficiently and functionally deliver therapeutic cargo. This is critical given the huge unmet need for novel treatment strategies for Alzheimers disease. This review summarizes and discusses the most recent findings in this field.

Neuroaxonal and cellular damageprotection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors.

Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D

Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimers Disease and neurodegeneration have not been elucidated. To examine association between physical function measures and plasma markers of Alzheimers Disease (AD) and neurodegeneration. Cross-sectional and longitudinal analyses. Community-based cohort in the city of Framingham, Massachusetts. 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. Plasma Aβ40 and Aβ42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aβ isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results Grip strength at Exam-7 was associated with plasma Aβ40 (β -0.006, p-value 0.032) at Exam-7 and plasma total-tau (β -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS β -0.009, p 0.0005 FWS β -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers Aβ42 was not associated with function. Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Gfastats conversion, evaluation and manipulation of genome sequences using assembly graphs.

With the current pace at which reference genomes are being produced, the availability of tools that can reliably and efficiently generate genome assembly summary statistics has become critical. Additionally, with the emergence of new algorithms and data types, tools that can improve the quality of existing assemblies through automated and manual curation are required. We sought to address both these needs by developing gfastats, as part of the Vertebrate Genomes Project (VGP) effort to generate high-quality reference genomes at scale. Gfastats is a standalone tool to compute assembly summary statistics and manipulate assembly sequences in FASTA, FASTQ or GFA .gz format. Gfastats stores assembly sequences internally in a GFA-like format. This feature allows gfastats to seamlessly convert FAST to and from GFA .gz files. Gfastats can also build an assembly graph that can in turn be used to manipulate the underlying sequences following instructions provided by the user, while simultaneously generating key metrics for the new sequences. Gfastats is implemented in C. Precompiled releases (Linux, MacOS, Windows) and commented source code for gfastats are available under MIT licence at httpsgithub.comvgl-hubgfastats. Examples of how to run gfastats are provided in the GitHub. Gfastats is also available in Bioconda, in Galaxy (httpsassembly.usegalaxy.eu) and as a MultiQC module (httpsgithub.comewelsMultiQC). An automated test workflow is available to ensure consistency of software updates. Supplementary data are available at Bioinformatics online.

Exploring electrophysiological markers of auditory predictive processes and pathological ageing in adults with Downs syndrome.

Downs syndrome is associated with pathological ageing and a propensity for early-onset Alzheimers disease. The early symptoms of dementia in people with Downs syndrome may reflect frontal lobe vulnerability to amyloid deposition. Auditory predictive processes rely on the bilateral auditory cortices with the recruitment of frontal cortices and appear to be impaired in pathologies characterized by compromised frontal lobe. Hence, auditory predictive processes were investigated to assess Downs syndrome pathology and its relationship with pathological ageing. An auditory electroencephalography (EEG) global-local paradigm was presented to the participants, in which oddball stimuli could either violate local or higher level global rules. We characterised predictive processes in individuals with Downs syndrome and their relationship with pathological ageing, with a focus on the EEG event-related potential called Mismatch Negativity (MMN) and the P300. In Downs syndrome, we also evaluated the EEG components as predictor of cognitive decline 1 year later. We found that predictive processes of detection of auditory violations are overall preserved in Downs syndrome but also that the amplitude of the MMN to local deviancies decreases with age. However, the 1-year follow-up of Downs syndrome found that none of the ERPs measures predicted subsequent cognitive decline. The present study provides a novel characterization of electrophysiological markers of local and global predictive processes in Downs syndrome.

Classifying the lifestyle status for Alzheimers disease from clinical notes using deep learning with weak supervision.

Since no effective therapies exist for Alzheimers disease (AD), prevention has become more critical through lifestyle status changes and interventions. Analyzing electronic health records (EHRs) of patients with AD can help us better understand lifestyles effect on AD. However, lifestyle information is typically stored in clinical narratives. Thus, the objective of the study was to compare different natural language processing (NLP) models on classifying the lifestyle statuses (e.g., physical activity and excessive diet) from clinical texts in English. Based on the collected concept unique identifiers (CUIs) associated with the lifestyle status, we extracted all related EHRs for patients with AD from the Clinical Data Repository (CDR) of the University of Minnesota (UMN). We automatically generated labels for the training data by using a rule-based NLP algorithm. We conducted weak supervision for pre-trained Bidirectional Encoder Representations from Transformers (BERT) models and three traditional machine learning models as baseline models on the weakly labeled training corpus. These models include the BERT base model, PubMedBERT (abstracts full text), PubMedBERT (only abstracts), Unified Medical Language System (UMLS) BERT, Bio BERT, Bio-clinical BERT, logistic regression, support vector machine, and random forest. The rule-based model used for weak supervision was tested on the GSC for comparison. We performed two case studies physical activity and excessive diet, in order to validate the effectiveness of BERT models in classifying lifestyle status for all models were evaluated and compared on the developed Gold Standard Corpus (GSC) on the two case studies. The UMLS BERT model achieved the best performance for classifying status of physical activity, with its precision, recall, and F-1 scores of 0.93, 0.93, and 0.92, respectively. Regarding classifying excessive diet, the Bio-clinical BERT model showed the best performance with precision, recall, and F-1 scores of 0.93, 0.93, and 0.93, respectively. The proposed approach leveraging weak supervision could significantly increase the sample size, which is required for training the deep learning models. By comparing with the traditional machine learning models, the study also demonstrates the high performance of BERT models for classifying lifestyle status for Alzheimers disease in clinical notes.

Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.

Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimers disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Students two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P 0.0038 Glutamic acid, P 0.0348 Alanine, P 0.0037 Glycine, P 0.0104), with concordant upregulation of mTORC1 activity phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001 phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P 0.0015 and inhibition of autophagosome formation microtubule-associated protein light chain 3 II (LC3 II), P 0.0073 LC3 puncta, P < 0.0001. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1amino acidmTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia.

Frontotemporal dementia is characterized by progressive atrophy of frontal andor temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n 9) or with mutations in the MAPT gene (n 13) with non-demented controls (n 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimers disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.

Blood-brain barrier penetration prediction enhanced by uncertainty estimation.

Blood-brain barrier is a pivotal factor to be considered in the process of central nervous system (CNS) drug development, and it is of great significance to rapidly explore the blood-brain barrier permeability (BBBp) of compounds in silico in early drug discovery process. Here, we focus on whether and how uncertainty estimation methods improve in silico BBBp models. We briefly surveyed the current state of in silico BBBp prediction and uncertainty estimation methods of deep learning models, and curated an independent dataset to determine the reliability of the state-of-the-art algorithms. The results exhibit that, despite the comparable performance on BBBp prediction between graph neural networks-based deep learning models and conventional physicochemical-based machine learning models, the GROVER-BBBp model shows greatly improvement when using uncertainty estimations. In particular, the strategy combined Entropy and MC-dropout can increase the accuracy of distinguishing BBB from BBB - to above 99% by extracting predictions with high confidence level (uncertainty score < 0.1). Case studies on preclinicalclinical drugs for Alzheimer s disease and marketed antitumor drugs that verified by literature proved the application value of uncertainty estimation enhanced BBBp prediction model, that may facilitate the drug discovery in the field of CNS diseases and metastatic brain tumors.

Efficacy of donepezil for the treatment of oxaliplatin-induced peripheral neuropathy DONEPEZOX, a protocol of a proof of concept, randomised, triple-blinded and multicentre trial.

The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimers disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade ≥ 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Flemings one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. NCT05254639 , clincialtrials.gov, Registered 24 February 2022.

A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model.

Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimers disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies. A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.

Diagnosis of Parkinson syndrome and Lewy-body disease using

We assessed The AUC was high with all ML methods (0.92-0.96) for high or low uptake. The AUC was the highest for symmetry or asymmetry with the kNN method (AUC 0.75) and the comma-dot feature with the GBT method (AUC 0.94). Based on the test data set, the diagnostic accuracy for a diagnosis of PSPDDLB was 0.86 ± 0.04 (SE), 0.87 ± 0.04, and 0.93 ± 0.02 for Models 1, 2 and 3, respectively. The AUC was optimal for Model 3, and significantly differed between Models 3 and 1 (p 0.027), and 3 and 2 (p 0.029). Image features such as high or low uptake, symmetry or asymmetry, and comma- or dot-like profiles can be determined using ML. The diagnostic accuracy of differentiating PSPDDLB was the highest for the multivariate model with three features and age compared with the conventional ROI-based method.

The performance of artificial intelligence-driven technologies in diagnosing mental disorders an umbrella review.

Artificial intelligence (AI) has been successfully exploited in diagnosing many mental disorders. Numerous systematic reviews summarize the evidence on the accuracy of AI models in diagnosing different mental disorders. This umbrella review aims to synthesize results of previous systematic reviews on the performance of AI models in diagnosing mental disorders. To identify relevant systematic reviews, we searched 11 electronic databases, checked the reference list of the included reviews, and checked the reviews that cited the included reviews. Two reviewers independently selected the relevant reviews, extracted the data from them, and appraised their quality. We synthesized the extracted data using the narrative approach. We included 15 systematic reviews of 852 citations identified. The included reviews assessed the performance of AI models in diagnosing Alzheimers disease (n 7), mild cognitive impairment (n 6), schizophrenia (n 3), bipolar disease (n 2), autism spectrum disorder (n 1), obsessive-compulsive disorder (n 1), post-traumatic stress disorder (n 1), and psychotic disorders (n 1). The performance of the AI models in diagnosing these mental disorders ranged between 21% and 100%. AI technologies offer great promise in diagnosing mental health disorders. The reported performance metrics paint a vivid picture of a bright future for AI in this field. Healthcare professionals in the field should cautiously and consciously begin to explore the opportunities of AI-based tools for their daily routine. It would also be encouraging to see a greater number of meta-analyses and further systematic reviews on performance of AI models in diagnosing other common mental disorders such as depression and anxiety.

The Effects of a Mixture of Cadmium, Lead, and Mercury on Metabolic Syndrome and Its Components, as well as Cognitive Impairment Genes, MicroRNAs, Transcription Factors, and Sponge Relationships The Effects of a Mixture of Cadmium, Lead, and Mercury on Metabolic Syndrome and Its Components, as well as Cognitive Impairment Genes, MicroRNAs, Transcription Factors, and Sponge Relationships.

Converging evidence indicates heavy metal-induced genes, transcription factors (TFs), and microRNAs (miRNAs) are critical pathological components of metabolic syndrome (MetS) and cognitive impairment. Thus, our goals are to identify the interaction of mixed heavy metals (cadmium lead mercury) with genes, TFs, and miRNAs involved in MetS and its components, as well as cognitive impairment development. The most commonly retrieved genes for each disease were different, but essential biological pathways such as oxidative stress, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, apoptosis, the IL-6 signaling pathway, and Alzheimers disease were highlighted. The genes CASP3, BAX, BCL2, IL6, TNF, APOE, HMOX1, and IGF were found to be mutually affected by the heavy metal mixture studied, suggesting the importance of apoptosis, inflammation, lipid, heme, and glucose metabolism in MetS and cognitive impairment, as well as the potentiality of targeting these genes in prospective therapeutic intervention for these diseases. EGR2, ATF3, and NFE2L2 were noted as the most key TFs implicated in the etiology of MetS and its components, as well as cognitive impairment. We also found six miRNAs induced by studied heavy metals were the mutual miRNAs linked to MetS, its components, and cognitive impairment. In particular, we used miRNAsong to construct and verify a miRNA sponge sequence for these miRNAs. These sponges are promising molecules for the treatment of MetS and its components, as well as cognitive impairment.

Evidence for preserved insulin responsiveness in the aging rat brain.

Insulin appears to exert salutary effects in the central nervous system (CNS). Thus, brain insulin resistance has been proposed to play a role in brain aging and dementia but is conceptually complex and unlikely to fit classic definitions established in peripheral tissues. Thus, we sought to characterize brain insulin responsiveness in young (4-5 months) and old (24 months) FBN male rats using a diverse set of assays to determine the extent to which insulin effects in the CNS are impaired with age. When performing hyperinsulinemic-euglycemic clamps in rats, intracerebroventricular (ICV) infusion of insulin in old animals improved peripheral insulin sensitivity by nearly two-fold over old controls and comparable to young rats, suggesting preservation of this insulin-triggered response in aging per se (p < 0.05). We next used an imaging-based approach by comparing ICV vehicle versus insulin and performed resting state functional magnetic resonance imaging (rs-fMRI) to evaluate age- and insulin-related changes in network connectivity within the default mode network. In aging, lower connectivity between the mesial temporal (MT) region and other areas, as well as reduced MT signal complexity, was observed in old rats, which correlated with greater cognitive deficits in old. Despite these stark differences, ICV insulin failed to elicit any significant alteration to the BOLD signal in young rats, while a significant deviation of the BOLD signal was observed in older animals, characterized by augmentation in regions of the septal nucleus and hypothalamus, and reduction in thalamus and nucleus accumbens. In contrast, ex vivo stimulation of hippocampus with 10 nM insulin revealed increased Akt activation in young (p < 0.05), but not old rats. Despite similar circulating levels of insulin and IGF-1, cerebrospinal fluid concentrations of these ligands were reduced with age. Thus, these data highlight the complexity of capturing brain insulin action and demonstrate preserved or heightened brain responses to insulin with age, despite dampened canonical signaling, thereby suggesting impaired CNS input of these ligands may be a feature of reduced brain insulin action, providing further rationale for CNS replacement strategies.

StatPearls

Memantine is an antagonist of the NMDA (N-Methyl-D-Aspartate)-receptor subtype of glutamate receptor. It is used to slow the neurotoxicity thought to be involved in Alzheimer disease and other neurodegenerative diseases.Memantine blocks the NMDA-receptor subtype of glutamate receptors preventing over-activation of glutamine receptors while allowing the normal activity. Its blocking effects antagonize an overactive glutaminergic system in the central nervous system (CNS) which is thought to be involved in the neurotoxicity seen in Alzheimer disease. This activity reviews the uses, indications, side effects and contraindications of memantine and highlights the role of the interprofessional team in the management of patients with dementia.

Circulating N-Acetylaspartate does not track brain NAA concentrations, cognitive function or features of small vessel disease in humans.

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N 824). In dataset 2, brain

Scalar on time-by-distribution regression and its application for modelling associations between daily-living physical activity and cognitive functions in Alzheimers Disease.

Wearable data is a rich source of information that can provide a deeper understanding of links between human behaviors and human health. Existing modelling approaches use wearable data summarized at subject level via scalar summaries in regression, temporal (time-of-day) curves in functional data analysis (FDA), and distributions in distributional data analysis (DDA). We propose to capture temporally local distributional information in wearable data using subject-specific time-by-distribution (TD) data objects. Specifically, we develop scalar on time-by-distribution regression (SOTDR) to model associations between scalar response of interest such as health outcomes or disease status and TD predictors. Additionally, we show that TD data objects can be parsimoniously represented via a collection of time-varying L-moments that capture distributional changes over the time-of-day. The proposed method is applied to the accelerometry study of mild Alzheimers disease (AD). We found that mild AD is significantly associated with reduced upper quantile levels of physical activity, particularly during morning hours. In-sample cross validation demonstrated that TD predictors attain much stronger associations with clinical cognitive scales of attention, verbal memory, and executive function when compared to predictors summarized via scalar total activity counts, temporal functional curves, and quantile functions. Taken together, the present results suggest that SOTDR analysis provides novel insights into cognitive function and AD.

Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons.

Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1

Amyloid fil rouge from invertebrate up to human ageing A focus on Alzheimer disease.

Amyloid fibrils and fibril-like structures are currently estimated to represent many different products of several genes in humans and play a key role in many types of proteinopathies, commonly associated with ageing process. They share the mutual feature of aggregation-prone proteins and the building up of molecular-supramolecular structure, such as inter-neuronal plaques in the brain of Alzheimers Disease (AD) patients, characterized by an extraordinary strength. Noteworthy, this type of structure has been reported in different organisms, in particular in invertebrates. The aim of the current review is to focus on alpha and beta amyloids i.e., SAAs, SAP and APP, elucidating the structure and function of amyloid proteins in invertebrates (such as nematods, annelids, molluscs, insects, ascidians) and highlighting their striking pattern of functional conservation when compared to human amyloid-like fibrils, thus focusing on possible new studies and applications for innovative therapies, particularly for AD, the most common and worldwide type of dementia.

Its You Caregiver and Clinician Perspectives on Lucidity in People Living With Dementia.

Episodes of lucidity (ELs), or a transient return of abilities believed to be lost in people living with dementia, are a growing area of interest. These events hold important implications for care, caregiving, and our understanding of underlying etiologies. Research on ELs is largely limited to retrospective reports. The perspectives of professional and family caregivers on ELs and research approaches can inform efforts to define and study lucidity. The present study examined family caregiver and hospice clinician experiences with and perspectives on ELs in people living with dementia and observational approaches to studying these events. This exploratory, descriptive qualitative study employed semistructured interviews (N 20 caregivers, N 6 clinicians). Data were analyzed using Rapid Identification of Themes and subsequent duplicate review of interview data to enhance trustworthiness. Most participants readily recalled events they perceived as ELs, describing a transient return of abilities they felt was significant andor meaningful. Defining features, interpretations, and the perceived impact of ELs varied, although ELs were commonly conceptualized as a manifestation of self. Caregivers described extensive efforts to detect patterns and supportive social conditions for ELs. Participants supported use of audiovisual observation to study ELs and provided recommendations for privacy, workflow, and caregiver engagement. Interpretations of ELs are heterogeneous, and recognition of these events may necessitate close familiarity with the person living with dementia. Participants endorse observational approaches and integration of caregivers in this research.

The shared genetic architecture of modifiable risk for Alzheimers disease a genomic structural equation modelling study.

Targeting modifiable risk factors may help to prevent Alzheimers disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention.

Genetic Association Between Epigenetic Aging-Acceleration and the Progression of Mild Cognitive Impairment to Alzheimers Disease.

Alzheimers disease (AD) is a progressive neurodegenerative disorder, and previous studies have shown its association with accelerated aging. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) that contributed to aging acceleration are also associated with the progression from mild cognitive impairment (MCI) to AD. By applying genetic correlation analysis and single-locus survival analysis, we investigated the associations between intrinsic- and extrinsic-epigenetic-age-acceleration (IEAA and EEAA) related SNPs and the progression time from MCI to AD dementia using the data of 767 MCI participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) study and 1 373 MCI patients from the National Alzheimers Coordinating Center (NACC) study. Genetic correlations were found between IEAAEEAA and AD (positive for IEAA-AD and negative for EEAA-AD). We revealed that 70 IEAA and 81 EEAA SNPs had associations with the progression time from MCI to AD with Bayesian false-discovery probability ≤ 0.8 in the ADNI study, with 22 IEAA SNPs and 16 EEAA SNPs being replicated in the NACC study (p < .05). Polygenic risk score (PRS) analysis showed that EEAA PRS but not IEAA PRS was associated with AD progression and the trend of decreasing fusiform gyrus volume in 2 data sets. Risk models incorporating both EAA PRSs did not show any significant improvement in predictive accuracy. Our results revealed multiple genetic variants with pleiotropic effects on both EAA and AD, which suggested shared genetic architecture between epigenetic age acceleration and AD progression.

Chondroitin sulfate proteoglycan is a potential target of memantine to improve cognitive function via the promotion of adult neurogenesis.

Chondroitin sulfate proteoglycan (CSPG) constitutes the neurogenic niche in the hippocampus. The reduction of hippocampal neurogenesis is involved in ageing-related cognitive decline and dementia. The purpose of this study is to find candidates that improve cognitive function by analysing the effects of memantine (MEM), a therapeutic agent for Alzheimers disease, on CSPG and adult hippocampal neurogenesis. The effects of MEM on neurogenesis-related cells and CSPG content were assessed in the hippocampus of middle-aged mice. The MEM-induced alterations in gene expressions of neurotrophins and enzymes associated with biosynthesis and degradation of CSPG in the hippocampus also were measured. The effects of MEM on cognitive function were estimated using a behavioural test battery. The same set of behavioural tests was applied to evaluate the effects of pharmacological depletion of CSPG in the hippocampus. The densities of newborn granule cells and content of CSPG in the hippocampus were increased by MEM. The expression levels of the enzyme responsible for the biosynthesis CSPG were increased by MEM. The neurotrophin-related molecules were activated by MEM. Short- and long-term memory performance was improved by MEM. Pharmacological depletion of CSPG impairs the effects of MEM on cognitive improvement in middle-aged mice. MEM regulates the biosynthesis and degradation of CSPG, which may underlie the improvement of cognitive function via the promotion of adult hippocampal neurogenesis. These results imply that CSPG-related enzymes potentially may be attractive candidates for the treatment of ageing-related cognitive decline.

The effect of framing on attitudes towards Alzheimers disease. A comparative study between younger and older adults.

The stigma and negative attitudes surrounding Alzheimers disease (AD) are reinforced by the prevalence of their negative representations. This study aimed to determine how AD framing influences attitudes towards AD and whether this influence differs between younger and older people. Additionally, the elaboration likelihood model (ELM) was used to examine the mediating role that emotions induced by different frames may have in bringing about attitude change. Posters with framed messages on AD (dualism and unity) were designed and shown to 136 participants (68 younger and 68 older adults). Both the younger and older participants were randomly divided into two sub-groups. Each sub-group was shown posters of a campaign with different AD frames one group viewed posters with messages of the dualism frame and the other group viewed posters with messages of the unity frame. To analyse the effect of the different frames, a mixed design of repeated measures (ANOVA) was used in which attitudes towards AD were measured on two occasions. Both the impact and the emotions produced by exposure to the messages were recorded after the presentation of the posters and a MANOVA test was performed on them. Attitudes, impact and emotions experienced by the younger and older participants were compared. Older adults displayed positive attitudes towards AD but less than younger people. Unity-framed messages produced a positive change in attitudes regardless of the audiences age and led to higher levels of happiness, whereas dualism-framed messages had a greater impact and produced feelings of sadness, anger and fear but did not change attitudes. These findings suggest that reframing of AD may be essential to achieve a positive attitudinal change in both younger and older populations and foster positive emotions. The use of unity-framed messages should be considered when developing and implementing policies targeted at communication and awareness of AD in order to reduce the stigma associated with this form of dementia.

Design, Synthesis, and Pharmacological Evaluation of

Alzheimers disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24

Social engagement and its links to cognition differ across non-Hispanic Black and White older adults.

Racial inequalities in dementia have been linked to disparities in socioeconomic status, chronic diseases, and psychosocial stress. Less focus has been given to psychosocial protective factors. Previous studies suggest that social engagement promotes better cognitive aging, but few have examined whether social engagement or its associations with cognition vary across non-Hispanic Whites (NHW) and Blacks (NHB). Participants included 465 adults (53% NHB) from the Michigan Cognitive Aging Project ( There were no racial differences in social network size or social support. NHB participants reported less social activity participation than NHW participants. Social activity participation was positively associated with memory in NHW, but not NHB. These findings may suggest a threshold effect whereby NHB older adults are less likely to participate in social activities at the level needed to yield cognitive benefits. Lower social activity participation among NHB may reflect structural barriers andor cultural differences in patterns of social engagement. This study highlights the need to improve measurement of and access to culturally relevant social activities for NHB to combat racial inequalities in cognitive aging. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Longitudinal trajectories and normative language standards in older adults with normal cognitive status.

To determine the longitudinal trajectories and normative standards of language in older adults. Participants were drawn from the cognitively normal (CN) subgroup of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort, a fairly representative cohort of the older Greek population. Language was assessed via semantic (SVF) and phonemic verbal fluency (PVF), Boston Naming Test-short form (BNT-sf), verbal comprehension and repetition, and a composite language z-score. Both baseline and longitudinal associations of language performance with age, sex, and education were explored with linear regression and generalized estimated equations. A total of 1,607 individuals (73.82 years ± 5.43, 60% women), with a mean educational attainment of 8.17 years (± 4.86) were CN at baseline. Baseline analysis revealed a continuum of language decline with higher age and lower educational attainment. Women performed better in composite and SVF tasks. A subgroup of 761 participants with available assessments after 3.07 years remained CN at follow-up. Each additional year of education mitigated composite language decline by .004 of a SD per year. Education additionally mitigated yearly reductions in SVF (by .049) and repetition (by .018) totals. Intriguingly, educational attainment was inversely related to the rate of PVF decline over time (β -.063). Women exhibited a more precipitous course of decline in SVF totals (.355 per year). Age was not related to differential rates of language decline in any measure. No significant longitudinal associations emerged for comprehension and BNT-sf. Lower educational attainment (but not aging) was associated with steeper language decline, mainly driven by SVF and verbal repetition. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Top-down and bottom-up sources of eye-movement guidance during realistic scene search in Alzheimers disease.

Visual search is a crucial task in daily life, but in Alzheimers disease (AD) it has usually been investigated using simple arrays. Here, we used scenes depicting real environments and studied the time course of attentional guidance. We analyzed eye-movement differences between mild AD patients and age-matched healthy controls during search. We examined top-down guidance, manipulating the target template (precise picture vs. word cue) and the target-scene semantic consistency (consistent vs. inconsistent), and bottom-up guidance, manipulating the perceptual salience (high vs. low) of targets and distractors. During scene scanning, AD patients had longer search times, made more fixations before the first target fixation, and showed a greater probability of distractor selection, with longer distractor fixation. AD also led to longer target fixation. In patients and controls, picture cues and highly salient targets improved all search phases, whereas consistent targets only improved search initiation (first saccade). Moreover, top-down and bottom-up guidance interacted in initiation and scanning, and this did not differ between the two groups of participants. However, AD led to a smaller picture cue benefit in shortening distractor fixation and greater bottom-up search facilitation during scanning, where a high-salience target reduced the performance gap between patients and controls. Our study shows the importance of top-down and bottom-up guidance, and their integration, in improving search in AD patients. It suggests that precise target cues and, even more, highly salient targets may act as environmental supports that enhance attentional processing and search performance. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Gait in cerebral small vessel disease, pre-dementia, and dementia A systematic review.

The interrelationships between gait, cerebral small vessel disease (CSVD), and cognitive impairments in aging are not well-understood-despite their common co-occurrence. To systematically review studies of gait impairment in CSVD, pre-dementia, and dementia, and to identify key gaps for future research and novel pathways toward intervention. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided search strategy was implemented in PubMed to identify relevant studies. Potential articles (n 263) published prior to 1 December 2021 were screened by two reviewers. Studies with sample sizes >20 and including some adults over > 65 years (n 202) were included. The key findings were that (1) adverse gait and cognitive outcomes were associated with several (rather than select) CSVD pathologies distributed across the brain, and (2) poor gait and CSVD pathologies were more strongly associated with dementia with a vascular, rather than an Alzheimers disease-related, cause. A better understanding of the interrelationships between gait performance in CSVD, pre-dementia, and dementia requires studies examining (1) comprehensive patterns in the clinical manifestations of CSVD, (2) raciallyethnically diverse samples, (3) samples followed for extended periods of time or across the adult life span, (4) non-traditional CSVD neuroimaging markers (e.g. resting-state functional magnetic resonance imaging (fMRI)), and (5) continuous (e.g. wearable sensors) and complex (e.g. dual-task) walking performance.

Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders.

Long intergenic noncoding RNAs (lincRNAs) are a class of independently transcribed molecules longer than 200 nucleotides that do not overlap known protein-coding genes. LincRNAs have diverse roles in gene expression and participate in a spectrum of biological processes. Dysregulation of lincRNA expression can abrogate cellular homeostasis, cell differentiation, and development and can also deregulate the immune and nervous systems. A growing body of literature indicates their important and multifaceted roles in the pathogenesis of several different diseases. Furthermore, certain lincRNAs can be considered potential therapeutic targets and valuable diagnostic or prognostic biomarkers capable of predicting the onset of a disease, its degree of activity, or the progression phase. In this review, we discuss possible mechanisms and molecular functions of lincRNAs in the pathogenesis of selected autoimmune and neurodegenerative disorders multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögrens syndrome, Huntingtons disease, Parkinsons disease, Alzheimers disease, and amyotrophic lateral sclerosis. This summary can provide new ideas for future research, diagnosis, and treatment of these highly prevalent and devastating diseases.

Prion strains shining new light on old concepts.

Prion diseases are a group of inevitably fatal neurodegenerative disorders affecting numerous mammalian species, including humans. The existence of heritable phenotypes of disease in the natural host suggested that prions exist as distinct strains. Transmission of sheep scrapie to rodent models accelerated prion research, resulting in the isolation and characterization of numerous strains with distinct characteristics. These strains are grouped into categories based on the incubation period of disease in different strains of mice and also by how stable the strain properties were upon serial passage. These classical studies defined the host and agent parameters that affected strain properties, and, prior to the advent of the prion hypothesis, strain properties were hypothesized to be the result of mutations in a nucleic acid genome of a conventional pathogen. The development of the prion hypothesis challenged the paradigm of infectious agents, and, initially, the existence of strains was difficult to reconcile with a protein-only agent. In the decades since, much evidence has revealed how a protein-only infectious agent can perform complex biological functions. The prevailing hypothesis is that strain-specific conformations of PrP

Blood-based Aβ42 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects opening new avenues for prevention.

Blood-based (BB) biomarkers for Aβ and tau can indicate pathological processes in the brain, in the early pathological, even pre-symptomatic stages in Alzheimers disease. However, the relation between BB biomarkers and AD-related processes in the brain in the earliest pre-pathology stage before amyloid pathology develops, and their relation with total brain concentrations of Aβ and tau, is poorly understood. This stage presents a critical window for the earliest prevention of AD. Preclinical models with well-defined temporal progression to robust amyloid and tau pathology provide a unique opportunity to study this relation and were used here to study the link between BB biomarkers with AD-related processes in pre- and pathological stages. We performed a cross-sectional study at different ages assessing the link between BB concentrations and AD-related processes in the brain. This was complemented with a longitudinal analysis and with analysis of age-related changes in a small cohort of human subjects. We found that BB-tau concentrations increased in serum, correlating with progressive development of tau pathology and with increasing tau aggregates and p-tau concentrations in brain in TauP301S mice (PS19) developing tauopathy. BB-Aβ42 concentrations in serum decreased between 4.5 and 9 months of age, correlating with the progressive development of robust amyloid pathology in APPPS1 (5xFAD) mice, in line with previous findings. Most importantly, BB-Aβ42 concentrations significantly increased between 1.5 and 4.5 months, i.e., in the earliest pre-pathological stage, before robust amyloid pathology develops in the brain, indicating biphasic BB-Aβ42 dynamics. Furthermore, increasing BB-Aβ42 in the pre-pathological phase, strongly correlated with increasing Aβ42 concentrations in brain. Our subsequent longitudinal analysis of BB-Aβ42 in 5xFAD mice, confirmed biphasic BB-Aβ42, with an initial increase, before decreasing with progressive robust pathology. Furthermore, in human samples, BB-Aβ42 concentrations were significantly higher in old (> 60 years) compared to young (< 50 years) subjects, as well as to age-matched AD patients, further supporting age-dependent increase of Aβ42 concentrations in the earliest pre-pathological phase, before amyloid pathology. Also BB-Aβ40 concentrations were found to increase in the earliest pre-pathological phase both in preclinical models and human subjects, while subsequent significantly decreasing concentrations in the pathological phase were characteristic for BB-Aβ42. Together our data indicate that BB biomarkers reflect pathological processes in brain of preclinical models with amyloid and tau pathology, both in the pathological and pre-pathological phase. Our data indicate a biphasic pattern of BB-Aβ42 in preclinical models and a human cohort. And most importantly, we here show that BB-Aβ increased and correlated with increasing concentrations of Aβ in the brain, in the earliest pre-pathological stage in a preclinical model. Our data thereby identify a novel critical window for prevention, using BB-Aβ as marker for accumulating Aβ in the brain, in the earliest pre-pathological stage, opening new avenues for personalized early preventive strategies against AD, even before amyloid pathology develops.

A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A).

The CACNA1C and the ZNF804A genes are among the most relevant schizophrenia GWAS findings. Recent evidence shows that the interaction of these genes with the schizophrenia diagnosis modulates brain functional response to a verbal fluency task. To better understand how these genes might influence the risk for schizophrenia, we aimed to study the interplay between CACNA1C and ZNF804A on working memory brain functional correlates. The analyses included functional and behavioural N-back task data (obtained from an fMRI protocol) and CACNA1C-rs1006737 and ZNF804A-rs1344706 genotypes for 78 healthy subjects and 78 patients with schizophrenia (matched for age, sex and premorbid IQ). We tested the effects of the epistasis between these genes as well as of the three-way interaction (CACNA1C × ZNAF804A × diagnosis) on working memory-associated activity (N-back 2-back vs 1-back). We detected a significant CACNA1C × ZNAF804A interaction on working memory functional response in regions comprising the ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula. The individuals with the GWAS-identified risk genotypes (CACNA1C-AAAG and ZNF804A-AA) displayed a reduced working memory modulation response. This genotypic combination was also associated with opposite brain activity patterns between patients and controls. While further research will help to comprehend the neurobiological mechanisms of this interaction, our data highlight the role of the epistasis between CACNA1C and ZNF804A in the functional mechanisms underlying the pathophysiology of schizophrenia.

Perceptions of Research Burden and Retention Among Participants in ADRC Cohorts.

Alzheimer disease (AD) and related dementias clinical research is associated with significant participant burden. The Perceived Research Burden Assessment (PeRBA) measures participants perceptions of logistical, psychological, and physical burdens. The purpose of this study was to assess PeRBAs psychometric properties, perceptual sources, and behavioral consequences with participants in a multisite study of participant retention in longitudinal cohort studies of Alzheimer disease and related dementias. Multicenter mixed methods. In-person or phone. A total of 443 participants at 4 NIA-funded Alzheimer Disease Research Centers (ADRCs) were randomly selected and invited to participate if they were 45 years of age or more, enrolled in longitudinal studies, and had a Clinical Dementia Rating Scale global score ≤1. Participants completed a 20-minute survey including the 21-item PeRBA about their research participation. PeRBA demonstrated high-internal consistency and convergent validity. PeRBA scores correlated with expected perceptual factors. Higher PeRBA scores were associated with lower attendance and higher dropout rates. PeRBA can be used by researchers to identify participants who may feel overburdened and tailor approaches and strategies to support participants in longitudinal AD studies, maximizing participation, and reducing dropout. Making efforts to increase participants understanding of study procedures, and building and maintaining trust throughout the study, can contribute to reducing perceived burden and potentially increasing retention in longitudinal AD studies.

Development of potent cholinesterase inhibitors based on a marine pharmacophore.

The management of neurological disorders such as dementia associated with Alzheimers or Parkinsons disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. Fourteen small inhibitors were designed based on recent discoveries about the inhibitory potential of a range of related marine secondary metabolites. The compounds were evaluated, in kinetic enzymatic assays, for their ability to inhibit three different cholinesterase enzymes and it was shown that compounds with a high inhibitory activity towards electric eel and human recombinant acetylcholinesterase (IC

Isolation of Some Phenolic Compounds from Plantago subulata L. and Determination of Their Antidiabetic, Anticholinesterase, Antiepileptic and Antioxidant Activity.

In the current study, some phenolic compounds, including acteoside, isoacteoside, echinacoside, and arenarioside purified and characterized from Plantago subulata. These compounds were tested for its antioxidant potential, including Fe

Bis-iodine-labeled Curcumin as a Potential CT Imaging Agent for β-amyloid Plaques in the Brain.

Alzheimers disease (AD) is one of the most common causes of dementia, affecting many old people. By designing and synthesizing intracerebral imaging probes, we try to provide a new solution for early diagnosis of AD. We designed and synthesized bis-iodine-labeled curcumin, and verified its performance through in vivo and in vitro experiments. In this study, bis-iodine-labeled curcumin (7, BICUR) was synthesized. In the in vitro mass spectrum binding assay, Kd values of BICUR with Aβ1-40 and Aβ1-42 aggregates were 46.29 nM and 64.29 nM, respectively. Aβ plaques in AD brain adjacent sections were positively stained by BICUR, which was similar to some other curcumin derivatives. The LogP value of BICUR was 1.45. In the biodistribution experiment, BICUR showed the highest initial brain uptake (5.87% compared with the blood concentration) two minutes after the tail vein injection and rapid clearance from the mouse brain. In the acute toxicity experiment, BICUR showed low toxicity, and the LD50 was > 100 mgkg. Moreover, BICUR showed a high stability in vitro (86.68% unchanged BICUR after incubation for 120 min in mouse brain homogenate). Besides, BICUR produced an enhanced CT imaging effect that could be sensitively detected in vitro, but it also showed an obvious differentiation from surrounding tissues after intracerebral injection. All results suggested that BICUR could probably act as a targeted CT imaging agent for Aβ plaques in the brain.

Automated detection of mild cognitive impairment and dementia from voice recordings A natural language processing approach.

Automated computational assessment of neuropsychological tests would enable widespread, cost-effective screening for dementia. A novel natural language processing approach is developed and validated to identify different stages of dementia based on automated transcription of digital voice recordings of subjects neuropsychological tests conducted by the Framingham Heart Study (n 1084). Transcribed sentences from the test were encoded into quantitative data and several models were trained and tested using these data and the participants demographic characteristics. Average area under the curve (AUC) on the held-out test data reached 92.6%, 88.0%, and 74.4% for differentiating Normal cognition from Dementia, Normal or Mild Cognitive Impairment (MCI) from Dementia, and Normal from MCI, respectively. The proposed approach offers a fully automated identification of MCI and dementia based on a recorded neuropsychological test, providing an opportunity to develop a remote screening tool that could be adapted easily to any language.

Alzheimers disease (AD) does not always mean amyloid positivity. We performed 3.0-T magnetic resonance imaging, The 164 patients included 23 (14.0%) who were amyloid-negative (age 74.9±8.3 years, mean±standard deviation 9 males, 14 females). Amyloid-negative patients were older, had a higher prevalence of diabetes mellitus, and had better visuospatial and memory functions. The frequency of the apolipoprotein E ε4 allele was higher and the hippocampal volume was smaller in amyloid-positive patients. Approximately 70% of the patients with amyloid-negative AD showed abnormal

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimers Disease.

Oral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimers disease (AD). This prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose patients in each stratum were randomized to the test and control groups at a 11 ratio. The difference between the control group and the IPI-301 group, quantified as the Hodges-Lehmann estimate of location shift, was 0.00 (95% confidence interval -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimers Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups ( IPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

Promising Blood Biomarkers for Clinical Use in Alzheimers Disease A Focused Update.

Alzheimers disease (AD) is the most-common cause of neurodegenerative dementia, and it is characterized by abnormal amyloid and tau accumulation, which indicates neurodegeneration. AD has mostly been diagnosed clinically. However, ligand-specific positron emission tomography (PET) imaging, such as amyloid PET, and cerebrospinal fluid (CSF) biomarkers are needed to accurately diagnose AD, since they supplement the shortcomings of clinical diagnoses. Using biomarkers that represent the pathology of AD is essential (particularly when disease-modifying treatment is available) to identify the corresponding pathology of targeted therapy and for monitoring the treatment response. Although imaging and CSF biomarkers are useful, their widespread use is restricted by their high cost and the discomfort during the lumbar puncture, respectively. Recent advances in AD blood biomarkers shed light on their future use for clinical purposes. The amyloid β (Aβ)42Aβ40 ratio and the concentrations of phosphorylated tau at threonine 181 and at threonine 217, and of neurofilament light in the blood were found to represent the pathology of Aβ, tau, and neurodegeneration in the brain when using automatic electrochemiluminescence technologies, single-molecule arrays, immunoprecipitation coupled with mass spectrometry, etc. These blood biomarkers are imminently expected to be incorporated into clinical practice to predict, diagnose, and determine the stage of AD. In this review we focus on advancements in the measurement technologies for blood biomarkers and the promising biomarkers that are approaching clinical application. We also discuss the current limitations, the needed further investigations, and the perspectives on their use.

Potential of Transcranial Direct Current Stimulation in Alzheimers Disease Optimizing Trials Toward Clinical Use.

Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive method for stimulating the brain that is rapidly developing into a treatment method for various neurological and psychiatric conditions. In particular, there is growing evidence of a therapeutic role for tDCS in ameliorating or delaying the cognitive decline in Alzheimers disease (AD). We provide a brief overview of the current development and application status of tDCS as a nonpharmacological therapeutic method for AD and mild cognitive impairment (MCI), summarize the levels of evidence, and identify the improvements needed for clinical applications. We also suggest future directions for large-scale controlled clinical trials of tDCS in AD and MCI, and emphasize the necessity of identifying the mechanistic targets to facilitate clinical applications.

Chronic Noise Exposure and Risk of Dementia A Systematic Review and Dose-Response Meta-Analysis.

Evidence is scarce about the effect of noise exposure on the risk of dementia. We conducted a systematic review and dose-response meta-analysis, aiming to explore the association between noise exposure and the risk of dementia. We searched PubMed, EMBASE and the Cochrane Library to collect studies on chronic noise exposure and the risk of dementia from database inception to September 18, 2021 without language limitations. Two authors independently screened the literature, extracted data and assessed the risk of bias of the included studies. A dose-response meta-analysis and subgroup analysis were then conducted to detect the association between noise exposure and the risk of dementia by using Stata 14.0 software. This study is registered on PROSPERO (CRD42021249243). A total of 11 studies were eligible for qualitative synthesis, and nine were eligible for quantitative data synthesis. All of them showed moderate to high quality scores in the assessment of risk of bias. We found a positive linear association between the noise increment and dementia risk ( Based on the current evidence, exposure to noise may be a specific risk factor for dementia. To better prevent dementia, more rigorously designed studies are needed to explore the etiological mechanism of noise and dementia.

Fruit and Vegetable Consumption and Cognitive Disorders in Older Adults A Meta-Analysis of Observational Studies.

The aim of this meta-analysis was to assess the quantitative associations between fruit and vegetable intake and cognitive disorders in older adults. A meta-analysis. We used the PubMed, Web of Science and Scopus databases for a literature search to 12 April 2022. We preliminarily retrieved 11,759 studies, 16 of which met the inclusion criteria including six cross-sectional studies, nine cohort studies and one case-control study, incorporating 64,348 participants and 9,879 cases. Using the three databases, we identified observational studies exploring the association. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Sixteen studies were included in the meta-analysis, and the results showed that increased fruit and vegetable consumption in older adults was associated with a decline in the prevalence of cognitive disorders (OR 0.79, 95% CI 0.76-0.83). Moreover, intake of fruits (OR 0.83, 95% CI 0.77-0.89) and vegetables (OR 0.75, 95% CI 0.70-0.80) alone were both associated with a lower prevalence of cognitive disorders. Subgroup analyses indicated that the intake of fruits and vegetables was associated with the prevalence of cognitive impairment (OR 0.72, 95% CI 0.76-0.80) and dementia (OR 0.84, 95% CI 0.78-0.91) but not Alzheimers disease (OR 0.88, 95% CI 0.76-1.01). Our meta-analysis provides evidence that the intake of fruits and vegetables is inversely proportional and linearly associated with the prevalence of cognitive disorders in older adults. Future research is required to further investigate the preventive effects of the frequency, quantity, and duration of eating vegetables and fruits on cognitive disorders in older adults.

The Kappa Opioid Receptor A Promising Therapeutic Target for Multiple Pathologies.

Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimers disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein-biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.

Organelle Interaction and Drug Discovery Towards Correlative Nanoscopy and Molecular Dynamics Simulation.

The inter-organelle interactions, including the cytomembrane, endoplasmic reticulum, mitochondrion, lysosome, dictyosome, and nucleus, play the important roles in maintaining the normal function and homeostasis of cells. Organelle dysfunction can lead to a range of diseases (e.g., Alzheimers disease (AD), Parkinsons disease (PD), and cancer), and provide a new perspective for drug discovery. With the development of imaging techniques and functional fluorescent probes, a variety of algorithms and strategies have been developed for the ever-improving estimation of subcellular structures, organelle interaction, and organelle-related drug discovery with accounting for the dynamic structures of organelles, such as the nanoscopy technology and molecular dynamics (MD) simulations. Accordingly, this work summarizes a series of state-of-the-art examples of the recent progress in this rapidly changing field and uncovering the drug screening based on the structures and interactions of organelles. Finally, we propose the future outlook for exciting applications of organelle-related drug discovery, with the cooperation of nanoscopy and MD simulations.

Brain functional topology differs by sex in cognitively normal older adults.

Late onset Alzheimers disease (AD) is the most common form of dementia, in which almost 70% of patients are women. We hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women. We studied cognitively healthy individuals from the Alzheimers Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the globalregional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein APOE E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed. Women had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men. Women overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD. Two thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes.

The Combination of Salidroside and Hedysari Radix Polysaccharide Inhibits Mitochondrial Damage and Apoptosis via the PKCERK Pathway.

Beta-amyloid (A This study aims to investigate the neuroprotective effects and pharmacological mechanisms of CSH on A HT22 cells were pretreated with various concentrations of salidroside or HRP for 24 h, followed by exposed to 20 CSH treatment increased cell viability, MMP, and decreased ROS generation in A CSH treatment have protective effects against A

Network Pharmacology-Based Strategy to Investigate the Pharmacologic Mechanisms of Coptidis Rhizoma for the Treatment of Alzheimers Disease.

Alzheimers disease (AD) is becoming a more prevalent public health issue in todays culture. The experimental study of Coptidis Rhizoma (CR) and its chemical components in AD treatment has been widely reported, but the principle of multi-level and multi-mechanism treatment of AD urgently needs to be clarified. This study focuses on network pharmacology to clarify the mechanism of CRs multi-target impact on Alzheimers disease. The Phytochemical-compounds of CR have been accessed from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) and Symmap database or HPLC determination. The values of Oral Bioavailability (OB) ≥ 30% and Drug Like (DL) ≥ 0.18 or blood ingredient were used to screen the active components of CR the interactive network of targets and compounds were constructed by STRING and Cytoscape platform, and the network was analyzed by Molecular Complex Detection (MCODE) Gene Ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) and metabolic pathway enrichment of targets were carried out with Metascape, the Database for Annotation, Visualization and Integrated Discovery (DAVID) and MetaboAnalyst platform Based on CytoHubba, the potential efficient targets were screened by Maximal Clique Centrality (MCC) and Degree, the correlation between potential efficient targets and amyloid β-protein (Aβ), Tau pathology was analyzed by Alzdata database, and the genes related to aging were analyzed by Aging Altas database, and finally, the core targets were obtained the binding ability between ingredients and core targets evaluated by molecular docking, and the clinical significance of core targets was assessed with Gene Expression Omnibus (GEO) database. 19 active components correspond to 267 therapeutic targets for AD, of which 69 is potentially effective in module analysis, RELA, TRAF2, STAT3, and so on are the critical targets of each module among the six core targets, RELA, MAPK8, STAT3, and TGFB1 have clinical therapeutic significance GO function, including 3050 biological processes (BP), 257 molecular functions (MF), 184 cellular components (CC), whose functions are mainly related to antioxidation, regulation of apoptosis and cell composition the HIF-1 signaling pathway, glutathione metabolism is the most significant result of 134 KEGG signal pathways and four metabolic pathways, respectively most of the active components have an excellent affinity in docking with critical targets. The pharmacological target prediction of CR based on molecular network pharmacology paves the way for a multi-level networking strategy. The study of CR in AD treatment shows a bright prospect for curing neurodegenerative diseases.

Depressive Symptoms Have Distinct Relationships With Neuroimaging Biomarkers Across the Alzheimers Clinical Continuum.

Depressive and anxiety symptoms are frequent in Alzheimers disease and associated with increased risk of developing Alzheimers disease in older adults. We sought to examine their relationships to Alzheimers disease biomarkers across the preclinical and clinical stages of the disease. Fifty-six healthy controls, 35 patients with subjective cognitive decline and 56 amyloid-positive cognitively impaired patients on the Alzheimers continuum completed depression and anxiety questionnaires, neuropsychological tests and neuroimaging assessments. We performed multiple regressions in each group separately to assess within group associations of depressive and anxiety symptoms with either cognition (global cognition and episodic memory) or neuroimaging data (gray matter volume, glucose metabolism and amyloid load). Depressive symptoms, but not anxiety, were higher in patients with subjective cognitive decline and cognitively impaired patients on the Alzheimers continuum compared to healthy controls. Greater depressive symptoms were associated with higher amyloid load in subjective cognitive decline patients, while they were related to higher cognition and glucose metabolism, and to better awareness of cognitive difficulties, in cognitively impaired patients on the Alzheimers continuum. In contrast, anxiety symptoms were not associated with brain integrity in any group. These data show that more depressive symptoms are associated with greater Alzheimers disease biomarkers in subjective cognitive decline patients, while they reflect better cognitive deficit awareness in cognitively impaired patients on the Alzheimers continuum. Our findings highlight the relevance of assessing and treating depressive symptoms in the preclinical stages of Alzheimers disease.

Behavioral Reserve in Behavioral Variant Frontotemporal Dementia.

Reserve refers to the individual clinical differences in response to a neuropathological burden. We explored the behavioral reserve (BR) and associated neural substrates in 40 participants with behavioral variant frontotemporal dementia (bvFTD) who were assessed with the frontal behavioral inventory (FBI) and magnetic resonance imaging. Because neuroimaging abnormality showed a high negative correlation with the FBI negative (but not positive) symptom scores, we developed a linear model only to calculate the nBR (BR for negative symptoms) marker using neuroimaging abnormalities and the FBI score. Participants were divided into high nBR and low nBR groups based on the nBR marker. The FBI negative symptom score was lower in the high nBR group than in the low nBR group having the same neuroimaging abnormalities. However, the high nBR group noted a steeper decline in cortical atrophy and showed less atrophy in the left frontotemporal cortices than the low nBR group. In addition, the fractional anisotropy (FA) values were greater in the high nBR than in the low nBR group, except in the sensory-motor and occipital areas. We identified an nBR-related functional network composed of bilateral frontotemporal areas and the left occipital pole. We propose the concept of BR in bvFTD, and these findings can help predict the disease progression.

Association of Plasma Neurofilament Light Chain With Glycaemic Control and Insulin Resistance in Middle-Aged Adults.

This study aimed to determine the association of plasma neurofilament light (NfL), a marker of neurodegeneration, with diabetes status and glycaemic parameters in people with normal glycaemia (NG), pre-diabetes (PD) and type 2 diabetes (T2D). Clinical and descriptive data for the diagnostic groups, NG (n30), PD (n48) and T2D (n29), aged between 40 and 75 years were included in this cross-sectional analysis. Plasma NfL levels were analyzed using the ultra-sensitive single-molecule array (Simoa) platform. A positive correlation was evident between plasma NfL and fasting glucose (r 0.2824 p 0.0032). Plasma NfL levels were not correlated with fasting insulin and insulin resistance. Plasma Nfl levels were significantly different across the diabetes groups (T2D >PD >NG, p0.0046). These results show biomarker evidence of neurodegeneration in adults at risk or with T2D. Larger sample size and longitudinal analysis are required to better understand the application of NfL in people with risk and overt T2D.

The WALLET Study Examining Early Memory Loss and Personal Finance.

This feasibility study tests a new approach for assessing personal finance in older persons with early memory loss. The project examines 2 primary outcomes that gauge the financial viability and well-being of older adults wealth loss and financial exploitation. The overall objective is to determine the association of financial literacy and management, financial decision-making, and cognition with wealth loss and financial exploitation. This cross-sectional study recruited 46 participants who were 60 years of age or older. Participants were classified as having mild cognitive impairment, perceived cognitive impairment, or no cognitive impairment. The study coordinator arranged with each participant to obtain copies of their main checking account statements for 12 consecutive months within the previous 2 years and, if appropriate, credit card statements. All statements were de-identified and assigned a random ID number. Participants then completed 2 telephone interviews. The average participant age was 72 years (standard deviation We demonstrate an alternative method for assessing personal finance using person-centered principles, which we believe are critical in the presence of diminished or impaired cognition. Our findings offer an innovative method for assessing the risk for wealth loss and financial exploitation.

Dynamic observations of various oligomers in amyloid

Acceleration of societal ageing has increased the global incidence of geriatric diseases such as Alzheimers disease (AD), and the demands for proper diagnosis and monitoring of those diseases are also increasing daily. We utilized diffracted X-ray blinking (DXB) for amyloid

Evolution, Expression and Functional Analysis of CXCR3 in Neuronal and Cardiovascular Diseases A Narrative Review.

Chemokines form a sophisticated communication network wherein they maneuver the spatiotemporal migration of immune cells across a system. These chemical messengers are recognized by chemokine receptors, which can trigger a cascade of reactions upon binding to its respective ligand. CXC chemokine receptor 3 (CXCR3) is a transmembrane G protein-coupled receptor, which can selectively bind to CXCL9, CXCL10, and CXCL11. CXCR3 is predominantly expressed on immune cells, including activated T lymphocytes and natural killer cells. It thus plays a crucial role in immunological processes like homing of effector cells to infection sites and for pathogen clearance. Additionally, it is expressed on several cell types of the central nervous system and cardiovascular system, due to which it has been implicated in several central nervous system disorders, including Alzheimers disease, multiple sclerosis, dengue viral disease, and glioblastoma, as well as cardiovascular diseases like atherosclerosis, Chronic Chagas cardiomyopathy, and hypertension. This review provides a narrative description of the evolution, structure, function, and expression of CXCR3 and its corresponding ligands in mammals and zebrafish and the association of CXCR3 receptors with cardiovascular and neuronal disorders. Unraveling the mechanisms underlying the connection of CXCR3 and disease could help researchers investigate the potential of CXCR3 as a biomarker for early diagnosis and as a therapeutic target for pharmacological intervention, along with developing robust zebrafish disease models.

Bipolar Disorder and Manic-like Symptoms in Alzheimers, Vascular and Frontotemporal Dementia A Systematic Review.

An increased risk of manic episodes has been reported in patients with neurodegenerative disorders, but the clinical features of bipolar disorder (BD) in different subtypes of dementia have not been thoroughly investigated. The main aim of this study is systematically review clinical and therapeutic evidence about manic syndromes in patients with Alzheimers disease (AD), vascular dementia (VD), and frontotemporal dementia (FTD). Since manic-mixed episodes have been associated with negative outcomes in patients with dementia and often require medical intervention, we also critically summarized selected studies with relevance for the treatment of mania in patients with cognitive decline. A systematic review of the literature was conducted according to PRISMA guidelines. PubMed, Scopus and Web of Science databases were searched up to February 2022. Sixty-one articles on patients with AD, VaD or FTD and BD or (hypo)mania have been included. Manic symptoms seem to be associated with disease progression in AD, have a greatly variable temporal relationship with cognitive decline in VaD, and frequently coincides with or precedes cognitive impairment in FTD. Overall, mood stabilizers and electroconvulsive therapy may be the most effective treatments, while the benefits of short-term treatment with antipsychotic agents must be balanced with the associated risks. Importantly, low-dose lithium salts may exert a neuroprotective activity in patients with AD. Prevalence, clinical features and treatment response to pharmacotherapy of manic syndromes in patients with dementia may be differentially affected by the nature of the underlying neurodegenerative conditions.

Terminal complement pathway activation drives synaptic loss in Alzheimers disease models.

Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimers disease. It is posited that C1 binding initiates complement activation on synapses C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps (i) is complement activated through to MAC at the synapse (ii) does MAC contribute to synaptic loss (iii) can MAC inhibition prevent synaptic loss Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and App

Asafoetida exerts neuroprotective effect on oxidative stress induced apoptosis through PI3KAktGSK3βNrf2HO-1 pathway.

Alzheimers Disease (AD) is a serious neurodegenerative disease and there is currently no effective treatment for AD progression. The use of TCM as a potential treatment strategy for AD is an evolving field of investigation. Asafoetida (ASF), an oleo-gum-resin isolated from Ferula assa-foetida root, has been proven to possess antioxidative potential and neuroprotective effects, which is closely associated with the neurological disorders. However, the efficacy and further mechanisms of ASF in AD experimental models are still unclear. A cognitive impairment of mouse model induced by scopolamine was established to determine the neuroprotective effects of ASF in vivo, as shown by behavioral tests, biochemical assays, Nissl staining, TUNEL staining, Immunohistochemistry, western blot and qPCR. Furthermore, the PC12 cells stimulated by H In vivo, ASF treatment significantly ameliorated cognitive impairment induced by scopolamine, as evidenced by improving learning and memory abilities, and reducing neuronal injury, cholinergic system impairment, oxidative stress and apoptosis in the hippocampus of mice. In vitro, our results validated that ASF can dose-dependently attenuated H Collectively, our work first uncovered the significant neuroprotective effect of ASF in treating AD in vivo. Then, we processed a series of vitro experiments to clarify the biological mechanism action. These data demonstrate that ASF can inhibit oxidative stress induced neuronal apoptosis to foster the prevention of AD both in vivo and in vitro, and it may exert the function of inhibiting AD through PI3KAktGSK3βNrf2HO-1pathway.

Role of Mitophagy in neurodegenerative Diseases and potential tagarts for Therapy.

Mitochondria dysfunction has been defined as one of the hallmarks of aging-related diseases as is characterized by the destroyed integrity, abnormal distribution and size, insufficient ATP supply, increased ROS production, and subsequently damage and oxidize the proteins, lipids and nucleic acid. Mitophagy, an efficient way of removing damaged or defective mitochondria by autophagy, plays a pivotal role in maintaining the mitochondrial quantity and quality control enabling the degradation of unwanted mitochondria, and thus rescues cellular homeostasis in response to stress. Accumulating evidence demonstrates that impaired mitophagy has been associated with many neurodegenerative diseases, such as Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD), amyotrophic lateral sclerosis (ALS) in a variety of patients and disease models with neural death, oxidative stress and disturbed metabolism, either as the cause or consequence. These findings suggest that modulation of mitophagy may be considered as a valid therapeutic strategy in neurodegenerative diseases. In this review, we summarize recent findings on the mechanisms of mitophagy and its role in neurodegenerative diseases, with a particular focus on mitochondrial proteins acting as receptors that mediate mitophagy in these diseases.

Molecular landscapes of human hippocampal immature neurons across lifespan.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents

Evaluation of

The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed by The analyses addressed (1) identification of an optimal The optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (r Treatment-related clinicaltrials.gov NCT01739348.

Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern.

Next to amyloid and tau, synaptic loss is a key pathological hallmark in Alzheimers disease, closely related to cognitive dysfunction and neurodegeneration. Tau is thought to cause synaptic loss, but this has not been experimentally verified in vivo. In a 2-year follow-up study, dual tracer PET-MR was performed in 12 amnestic MCI patients using

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimers disease.

Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. The degree of pial coverage correlates with macrophage density and phagocytosis of CSF tracer. In vivo imaging confirms transpial influx of CSF tracer, suggesting a role of pia in CSF filtration, but not flow restriction. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimers disease. Moreover, pial thickness correlates with improved CSF flow and reduced β-amyloid deposits in PVS of old mice. We show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

Preoperative Plasma Tau-PT217 and Tau-PT181 Are Associated With Postoperative Delirium.

This study aims to identify blood biomarkers of postoperative delirium. Phosphorylated tau at threonine 217 (Tau-PT217) and 181 (Tau-PT181) are new Alzheimer disease biomarkers. Postoperative delirium is associated with Alzheimer disease. We assessed associations between Tau-PT217 or Tau-PT181 and postoperative delirium. Of 491 patients (65 years old or older) who had a knee replacement, hip replacement, or laminectomy, 139 participants were eligible and included in the analysis. Presence and severity of postoperative delirium were assessed in the patients. Preoperative plasma concentrations of Tau-PT217 and Tau-PT181 were determined by a newly established Nanoneedle technology. Of 139 participants (73±6 years old, 55% female), 18 (13%) developed postoperative delirium. Participants who developed postoperative delirium had higher preoperative plasma concentrations of Tau-PT217 and Tau-PT181 than participants who did not. Preoperative plasma concentrations of Tau-PT217 or Tau-PT181 were independently associated with postoperative delirium after adjusting for age, education, and preoperative Mini-Mental State score odds ratio (OR) per unit change in the biomarker 2.05, 95% confidence interval (CI)1.61-2.62, P<0.001 for Tau-PT217 and OR 4.12 95% CI 2.55--6.67, P<0.001 for Tau-PT181. The areas under the receiver operating curve for predicting delirium were 0.969 (Tau-PT217) and 0.885 (Tau-PT181). The preoperative plasma concentrations of Tau-PT217 or Tau-PT181 were also associated with delirium severity beta coefficient (β) per unit change in the biomarker 0.14 95% CI 0.09-0.19, P<0.001 for Tau-PT217 and β 0.41 95% CI 0.12-0.70, P0.006 for Tau-PT181). Preoperative plasma concentrations of Tau-PT217 and Tau-PT181 were associated with postoperative delirium, with Tau-PT217 being a stronger indicator of postoperative delirium than Tau-PT181.

Association of Pace of Aging Measured by Blood-Based DNA Methylation With Age-Related Cognitive Impairment and Dementia.

DNA methylation algorithms are increasingly used to estimate biological aging however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimers Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults. We tested 3 generations of DNA methylation age algorithms (first generation Horvath and Hannum clocks second generation PhenoAge and GrimAge and third generation DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) Alzheimer disease and related dementias (ADRD) screening tests (Alzheimers Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia. In ADNI ( Third-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.

Development of high quality T

High-quality T

Irisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process.

Irisin is an exercise-induced myokine expressed as a bioactive peptide in multiple tissues and organs, and exercise and cold exposure are the major inducers for its secretion. Irisin presents a decreasing trend with the extension of age and is also closely associated with a wide range of aging-related diseases. Currently, many studies on irisin are being conducted with respect to physiological functions for health promotion, and the prevention, treatment and rehabilitation of chronic diseases, as well as mechanisms associated with improving energy metabolic balance, enhancing cellular homeostasis by optimizing autophagy, promoting mitochondrial quality control, reducing reactive oxygen species (ROS) production, and mitigating inflammatory responses. These diseases include metabolic diseases (obesity, type 2 diabetes, and bone metabolism) cardiovascular diseases (hypertension, coronary heart disease, cardiomyopathy and stroke) nervous system diseases (Alzheimers disease, Parkinsons disease, and stroke) and others (cancer and sarcopenia). Although the current studies on irisin are relatively extensive, some studies have produced unexplained experimental results. This article introduces an overview of the generation, secretion, and tissue distribution, of irisin, and its targeting of tissues or organs for the prevention and treatment of above-mentioned chronic diseases is systematically summarized, with discussion of the underlying molecular mechanisms. This study is expected to improve the understanding of irisin, which may be beneficial to identify novel and effective targets for the screening, diagnosis, or therapy of these chronic diseases, or develop promising interventional strategies, effective drug candidates, functional foods, or exercise mimetics.

The role of microRNA-485 in neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are age-related disorders characterized by progressive neurodegeneration and neuronal cell loss in the central nervous system. Neuropathological conditions such as the accumulation of misfolded proteins can cause neuroinflammation, apoptosis, and synaptic dysfunction in the brain, leading to the development of NDDs including Alzheimers disease (AD) and Parkinsons disease (PD). MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene expression post-transcriptionally via RNA interference. Recently, some studies have reported that some miRNAs play an important role in the development of NDDs by regulating target gene expression. MiRNA-485 (miR-485) is a highly conserved brain-enriched miRNA. Accumulating clinical reports suggest that dysregulated miR-485 may be involved in the pathogenesis of AD and PD. Emerging studies have also shown that miR-485 plays a novel role in the regulation of neuroinflammation, apoptosis, and synaptic function in the pathogenesis of NDDs. In this review, we introduce the biological characteristics of miR-485, provide clinical evidence of the dysregulated miR-485 in NDDs, novel roles of miR-485 in neuropathological events, and discuss the potential of targeting miR-485 as a diagnostic and therapeutic marker for NDDs.

Pharmacotherapy for Alzheimers disease whats new on the horizon

Alzheimers disease (AD) is a debilitating disease, with no cure. Recently, a monoclonal antibody (aducanumab) directed toward amyloid aggregates was approved as a disease-modifying treatment (DMT) for the disease. Other compounds (symptomatic or DMTs) are at different stages of clinical trial development. The authors conducted a search on PUBMED, MEDLINE, and clinicaltrials.gov for compounds in phase III clinical trials for cognitive impairment due to AD. Mechanisms of action and clinical trial data related to these compounds are discussed in this paper. There is an unmet need for both treatment approaches (symptomatic and DMTs) to improve outcomes in individuals at different stages of the AD continuum. Future trials with symptomatic therapies should rely on biomarkers to improve enrollment of participants with pure AD. More sensitive, innovative, and composite assessment tools should be used. Given the complexity and heterogeneity of AD, combining several DMTs with synergistic mechanisms of action is a promising approach to achieve a significant impact on reversing cognitive decline. We recommend testing DMTs early on in the disease continuum, even in asymptomatic individuals at risk for AD. Longer duration of follow-up in clinical trials with DMTs is recommended.

Alternative processing of human HTT mRNA with implications for Huntingtons disease therapeutics.

Huntington disease is caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that is translated into a polyglutamine stretch in the huntingtin protein (HTT). We previously showed that HTT mRNA carrying an expanded CAG repeat was incompletely spliced to generate HTT1a, an exon 1 only transcript, which was translated to produce the highly aggregation-prone and pathogenic exon 1 HTT protein. This occurred in all knock-in mouse models of Huntingtons disease and could be detected in patient cell lines and post-mortem brains. To extend these findings to a model system expressing human HTT, we took advantage of YAC128 mice that are transgenic for a yeast artificial chromosome carrying human HTT with an expanded CAG repeat. We discovered that the HTT1a transcript could be detected throughout the brains of YAC128 mice. We implemented RNAscope to visualize HTT transcripts at the single molecule level and found that full-length HTT and HTT1a were retained together in large nuclear RNA clusters, as well as being present as single transcripts in the cytoplasm. Homogeneous time-resolved fluorescence analysis demonstrated that the HTT1a transcript had been translated to produce the exon 1 HTT protein. The levels of exon 1 HTT in YAC128 mice, correlated with HTT aggregation, supportive of the hypothesis that exon 1 HTT initiates the aggregation process. Huntingtin-lowering strategies are a major focus of therapeutic development for Huntingtons disease. These approaches often target full-length HTT alone and would not be expected to reduce pathogenic exon 1 HTT levels. We have established YAC128 mouse embryonic fibroblast lines and shown that, together with our QuantiGene multiplex assay, these provide an effective screening tool for agents that target HTT transcripts. The effects of current targeting strategies on nuclear RNA clusters are unknown, structures that may have a pathogenic role or alternatively could be protective by retaining HTT1a in the nucleus and preventing it from being translated. In light of recently halted antisense oligonucleotide trials, it is vital that agents targeting HTT1a are developed, and that the effects of HTT-lowering strategies on the subcellular levels of all HTT transcripts and their various HTT protein isoforms are understood.

Oxygen Sensing in Neurodegenerative Diseases Current Mechanisms, Implication of Transcriptional Response, and Pharmacological Modulation.

Variation in Population Attributable Fraction of Dementia Associated With Potentially Modifiable Risk Factors by Race and Ethnicity in the US.

Identifying modifiable risk factors that are associated with dementia burden across racial and ethnic groups in the population can yield insights into the potential effectiveness of interventions in preventing dementia and reducing disparities. To calculate the population attributable fraction (PAF) of dementia associated with 12 established modifiable risk factors for all US adults, as well as separately by race and ethnicity. This cross-sectional study used survey data from nationally representative samples of US adults. PAFs were calculated using relative risks and prevalence estimates for 12 risk factors. Relative risks were taken from meta-analyses, as reported in a 2020 systematic review. Prevalence estimates for risk factors were derived from nationally representative cross-sectional survey data collected between 2011 and 2018. Combined PAFs were adjusted for risk factor communality using weights derived from the Atherosclerosis Risk in Communities (ARIC) study (1987-2018). Analyses were conducted May through October 2021. Low education, hearing loss, traumatic brain injury, hypertension, excessive alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and air pollution. PAF for each dementia risk factor, a combined PAF, and the decrease in the number of prevalent dementia cases in 2020 that would be expected given a 15% proportional decrease in each exposure. Among all US adults, an estimated 41.0% (95% CI, 22.7%-55.9%) of dementia cases were attributable to 12 risk factors. A 15% proportional decrease in each risk factor would reduce dementia prevalence in the population by an estimated 7.3% (95% CI, 3.7%-10.9%). The estimated PAF was greater for Black and Hispanic than it was for White and Asian individuals. The greatest attributable fraction of dementia cases was observed for hypertension (PAF, 20.2% 95% CI, 6.3%-34.4%), obesity (PAF, 20.9% 95% CI, 13.0%-28.8%), and physical inactivity (PAF, 20.1% 95% CI, 9.1%-29.6%). These factors were also highest within each racial and ethnic group, although the proportions varied. A large fraction of dementia cases in the US were associated with potentially modifiable risk factors, especially for Black and Hispanic individuals. Targeting and reducing these risk factors may curb the projected rise in dementia cases over the next several decades.

Laser tweezers Raman spectroscopy combined with machine learning for diagnosis of Alzheimers disease.

Alzheimers disease (AD) is a common nervous system disease to affect mostly elderly people over the age of 65 years. However, the diagnosis of AD is mainly depend on the imaging examination, clinical assessments and neuropsychological tests, which may get error diagnosis results and are not able to detect early AD. Here, a rapid, non-invasive, and high accuracy diagnostic method for AD especially early AD is provided based on the laser tweezers Raman spectroscopy (LTRS) combined with machine learning algorithms. AD platelets from different 3xTg-AD transgenic rats at different stages of disease are captured to collect high signal-to-noise ratio Raman signals without contact by LTRS, which is then combined with partial least squares discriminant analysis (PLS-DA), support vector machine (SVM) and principal component analysis (PCA)-canonical discriminate function (CDA) for classification. The results show that the normal and diseased platelets at 3-, 6- and 12-month AD are successfully distinguished and the accuracy is 91%, 68% and 97% respectively, which demonstrates the suggested method can provide a precise detection for AD diagnosis at early, middle and advanced stages.

Abeta-induced presynaptic release of UBC9 through extracellular vesicles involves SNAP23.

Ubiquitin conjugating enzyme 9 (UBC9), the sole small ubiquitin-like modifier(SUMO) conjugating enzyme, is considered to be a vital regulator of the mechanism of SUMOylation and is likely to participate in the progression of Alzheimers disease (AD). Our previous studies found that UBC9 is highly mobile in neurons, but the underlying mechanism is still unknown. We designed to investigate the underlying mechanism of the synaptic redistribution of UBC9 in AD. We found that β-amyloid peptide (Aβ) significantly decreased presynaptic UBC9 expression and increased postsynaptic UBC9 expression but did not affect UBC9 expression in synaptosomes. Moreover, there is evidence that extracellular vesicles (EVs) may facilitate synaptic gap transmission. Immunoprecipitation assays showed that flotillin, which is specifically expressed in EVs, co-immunoprecipitated with UBC9 in cell lysates and media and that Aβ treatment enhanced this interaction. Additionally, epidermal growth factor and oleanolic acid have been found to either promote or inhibit the release of EVs, thus blocking the Aβ-induced presynaptic release of UBC9. However, knockdown of synaptosome associated protein 23 (SNAP-23) or inhibition of SNAP23 phosphorylation was found to secure Aβ-induced presynaptic release of UBC9. These results suggest that Aβ induces redistribution of UBC9 from presynaptic to postsynaptic terminals, which may mediate through EVs associated with SNAP23. Our study reveals the cellular mechanisms of EVs as an essential component of the presynaptic release of UBC9.

Loss of body weight in old 5xFAD mice and the alteration of gut microbiota composition.

The cause of age-related body weight loss in Alzheimers disease (AD) is unclear. We compared the differences in food intake, malabsorption, locomotor activity, and gut microbiota composition between 5xFAD mice, a useful model of AD, and wild-type (WT) mice to investigate the mechanisms underlying lower body weight in 5xFAD mice. Fifteen-month-old male 5xFAD mice and age-matched WT mice were divided into four groups a control diet (CD) or a high-fat diet (HFD). After feeding CD or HFD for eight to nine weeks, 5xFAD mice had a significantly lower body weight than WT mice regardless of diet (p < 0.05). Additionally, the 5xFAD mice did not show a reduction in food intake compared to the WT mice regardless of diet. To evaluate malabsorption, we performed a fecal fat test. There was no obvious fecal fat in both the 5xFAD mice and WT mice. However, 5xFAD mice showed greater locomotor activity than WT mice in the Y-maze test. The comprehensive analysis of gut microbiota composition showed that 15-month-old 5xFAD mice had more Proteobacteria population and fewer Actinobacteria and Bifidobacteriales populations than WT mice. To investigate the effects of fructooligosaccharides (FOS), we administrated FOS to 15-month-old 5xFAD mice. FOS administration decreased Proteobacteria and increased Actinobacteria population, although that did not change Bifidobacteriales population. Moreover, cognitive impairment and body weight of 5xFAD mice were not changed by FOS administration. In conclusion, loss of body weight in 15-month-old 5xFAD mice might be partially derived from excess energy output by hyperactivity. Moreover, 15-month-old 5xFAD mice might have unique alteration of gut microbiota composition and the potential resistance to FOS.

Tannic acid inhibits lipopolysaccharide-induced cognitive impairment in adult mice by targeting multiple pathological features.

Tannic acid (TA) is a natural compound present abundantly in fruit such as grapes and green tea. In this study, we have evaluated the therapeutic efficacy of TA against Lipopolysaccharide (LPS)-induced oxidative stress-mediated memory impairment, neuroinflammation, insulin signaling impairment, and Amyloid Beta (Aβ) deposition in adult male mice. The LPS was administered once per week and TA twice a week to adult male mice for three months consecutively. Behavioral studies were performed using different behavioral models such as balance beam, novel object recognition (NOR), Morris water maze (MWM), and Y-maze tests. The protein expression of different mediators such as TNF-α, p-JNK, pIRS636, BACE1, APP, and Aβ was evaluated through western blot and immunofluorescence staining techniques. Biochemical assays were carried out to assess the antioxidant activities of TA. The computational study was conducted to predict the binding mode of TA with target sites of TNF-α. Behavioral studies showed that the TA-treated mice exhibited gradual memory improvement. TA significantly inhibited BACE1 activity and reduced production and accumulation of Aβ in the hippocampus of mice brains. Moreover, the TA significantly inhibited LPS-induced ROS production and enhanced the glutathione levels. Furthermore, we have shown via the computational method for the first time that TA inhibits LPS-triggered TNF-ὰ and its downstream signaling to reduce AD pathology including memory impairment, neuroinflammation, insulin signaling impairment, and Aβ deposition in adult mice. Taken together our current study demonstrates that TA is a potential candidate for the abrogation of LPS-induced neurotoxicity and AD pathology in rodents models.

Effects of Interleukin-6 Gene Knockout on β-amyloid Deposition and Cognition in 5×FAD Mouse Model of Alzheimers Disease.

Objective To explore the effects of interleukin-6 (IL-6) gene knockout on the cognitive function and pathological changes in 5×FAD transgenic mice of Alzheimers disease.Methods IL-6

Longitudinal changes in brain oxygen extraction fraction (OEF) in older adults Relationship to markers of vascular and Alzheimers pathology.

Oxygen extraction fraction (OEF) reflects the balance between oxygen delivery and consumption. We longitudinally measured OEF in older adults to examine the relationship with markers of Alzheimers disease (AD) and vascular pathology. One hundred thirty-seven participants were studied at two time-points at an interval of 2.16 years. OEF was measured using T OEF increased from baseline to follow-up. The increase in OEF was more prominent in individuals with high vascular risks compared to those with low vascular risks, and was associated with progression of vascular risks and the growth in WMH volume. OEF change was not related to CSF markers of AD pathology or their progression. Longitudinal OEF change in older adults is primarily related to vascular pathology.

Toward rational use of cognitive training in those with mild cognitive impairment.

The term cognitive training includes a range of techniques that hold potential for treating cognitive impairment caused by neurologic injury and disease. Our central premise is that these techniques differ in their mechanisms of action and therefore engage distinct brain regions (or neural networks). We support this premise using data from a single-blind randomized-controlled trial in which patients with mild cognitive impairment were randomized to either mnemonic strategy training (MST) or spaced retrieval training (SRT) as they learned ecologically relevant object-location associations. Both training approaches were highly effective in the short term, but MST demonstrated a clear advantage after days to weeks. MST also increased activation in and functional connectivity between frontal, temporal, and parietal regions as well as the hippocampus. In contrast, patterns of reduced activation and functional connectivity were evident following SRT. These findings support the rational development of cognitive training techniques.

Effect of chlorogenic acid plus donepezil on critical neurocortical enzyme activities, inflammatory markers, and synaptophysin immunoreactivity in scopolamine-assaulted rats, supported by multiple ligand simultaneous docking.

The effect of chlorogenic acid (a natural phenolic acid ubiquitous in plant foods) on selected therapeutic properties of donepezil (DON) in a scopolamine (SCOP)-induced rat model of amnesia was the focus of this study. Adult albino (Wister strain) rats were allocated into five groups (n 11) consisting of control, SCOP, SCOP chlorogenic acid (CGA), SCOP DON, and SCOP CGA DON for 7 days. Post-treatment, the rat brain cerebral cortex homogenate was assayed for cholinesterase and monoamine oxidase activities. Also, the reactive oxygen species, total thiol and nitric oxide contents, alongside catalase, and superoxide dismutase activities were determined. Routine histology for neuronal and glial cells as well as synaptophysin immunoreactivity was also carried out on the cerebral cortex. Thereafter, multiple ligand simultaneous docking was carried out for DON and CGA at the active sites of AChE and BChE. The results revealed that the biochemical parameters, glial cells, and synaptophysin immunoreactivity were significantly impaired in the cerebral cortex of scopolamine-treated rats. However, impaired butyrylcholinesterase and monoamine oxidase activity, together with antioxidant, glial cells, and synaptophysin levels were significantly ameliorated in scopolamine-treated rats administered DON CGA compared to donepezil alone. The docking of both DON and CGA at the active sites of AChE or BChE showed higher binding energy to both enzymes compared to individual interactions of either DON or CGA. Hence, this study has been able to show that CGA could improve some of the therapeutic effects of DON, which could broaden the therapeutic spectrum of this drug. PRACTICAL APPLICATIONS This study showed that chlorogenic acid (a major phenolic acid found in plant foods such as coffee) modulated some of the therapeutic properties of donepezil (an anticholinesterase drug used in the treatment of mild-to-moderate Alzheimers disease). The combinations elicited better anti-butyrylcholinesterase, antimonoamine oxidase, and antioxidant properties, thus presenting this food-drug interaction as potentially able to offer better therapeutic properties.

Efficacy and safety of sodium oligomannate in the treatment of Alzheimers disease.

To evaluate the efficacy and safety of sodium oligomannate in the treatment of Alzheimers disease. Patients with mild-to-moderate AD were randomly divided into three groups, the scores of ADAS-Cog, ADL, CIBIC-plus, NPI and CSDD were evaluated at the 0th, 12th, 24th, 36th and 48th weeks of medication. Comparing the mean scores of each scale in each cycle of each group. Using SPSS21.0 software for measurement data using t test, Chi-square test was used for counting data. A total of 72 patients with AD were included. The difference of CIBIC-plus score at week 12(P0.007) and 24(P0.005), ADAS-Cog scores (P0.01) at week 24 in GV-971 group was statistically significant compared with that in the control group. The CIBIC-plus score at week 24(P0.01) and week 48 (P0.04), CSDD scores at week 48(P0.02) of GV-971 group was statistically significant compared with that of donepezil group. There were 2 cases of adverse reaction of increased stool frequency in GV-971 (5.67%), and 2 cases of adverse reaction of nausea in donepezil group (8.33%), the difference was statistically significant. GV-971 is as effective as donepezil in the treatment of Alzheimers disease, and may even be better. It has good safety.

Intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases.

Many different intrinsically disordered proteins and proteins with intrinsically disordered regions are associated with neurodegenerative diseases. These types of proteins including amyloid-β, tau, α-synuclein, CHCHD2, CHCHD10, and G-protein coupled receptors are increasingly becoming evaluated as potential drug targets in the pharmaceutical-based treatment approaches. Here, we focus on the neurobiology of this class of proteins, which lie at the center of numerous neurodegenerative diseases, such as Alzheimers and Parkinsons diseases, Huntingtons disease, amyotrophic lateral sclerosis, frontotemporal dementia, Charcot-Marie-Tooth diseases, spinal muscular atrophy, and mitochondrial myopathy. Furthermore, we discuss the current treatment design strategies involving intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases. In addition, we emphasize that although the G-protein coupled receptors are traditionally investigated using structural biology-based models and approaches, current studies show that these receptors are proteins with intrinsically disordered regions and therefore they require new ways for their analysis.

Immunosenescence of brain accelerates Alzheimers disease progression.

Most of Alzheimers disease (AD) cases are sporadic and occur after age 65. With prolonged life expectancy and general population aging, AD is becoming a significant public health concern. The immune system supports brain development, plasticity, and homeostasis, yet it is particularly vulnerable to aging-related changes. Aging of the immune system, called immunosenescence, is the multifaceted remodeling of the immune system during aging. Immunosenescence is a contributing factor to various age-related diseases, including AD. Age-related changes in brain immune cell phenotype and function, crosstalk between immune cells and neural cells, and neuroinflammation work together to promote neurodegeneration and age-related cognitive impairment. Although numerous studies have confirmed the correlation between systemic immune changes and AD, few studies focus on the immune state of brain microenvironment in aging and AD. This review mainly addresses the changes of brain immune microenvironment in aging and AD. Specifically, we delineate how various aspects of the brain immune microenvironment, including immune gateways, immune cells, and molecules, and the interplay between immune cells and neural cells, accelerate AD pathogenesis during aging. We also propose a theoretical framework of therapeutic strategies selectively targeting the different mechanisms to restore brain immune homeostasis.

Virtual Screening and Testing of GSK-3 Inhibitors Using Human SH-SY5Y Cells Expressing Tau Folding Reporter and Mouse Hippocampal Primary Culture under Tau Cytotoxicity.

Glycogen synthase kinase-3β (GSK-3β) is an important serinethreonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimers disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamines screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (Tau

Proteomics and Population Biology in the Cardiovascular Health Study (CHS) design of a study with mentored access and active data sharing.

In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimers disease systematic review and meta-analysis.

Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimers disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice. To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimers disease. The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses. We included 19 randomised controlled trials (1811 patients), of which six were judged as good quality, seven as fair and six poor. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimers Disease Assessment Scale-Cognitive Subscale (standardised mean difference (SMD) 0.14, 95% CI 0.03 to 0.25, p0.01 I Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimers disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects. CRD42021277500.

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System.

Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular homeostasis of cholesterol they can pass across the membrane and vascular barriers and act distantly as para- and endocrine agents. A small amount of 25-hydroxycholesterol (25-HC) is produced in the endoplasmic reticulum of most cells, where it serves as a potent regulator of the synthesis, intracellular transport, and storage of cholesterol. Production of 25-HC is strongly increased in the macrophages, dendrite cells, and microglia at the inflammatory response. The synthesis of 25-HC can be also upregulated in some neurological disorders, such as Alzheimers disease, amyotrophic lateral sclerosis, spastic paraplegia type 5, and X-linked adrenoleukodystrophy. However, it is unclear whether 25-HC aggravates these pathologies or has the protective properties. The molecular targets for 25-HC are transcriptional factors (LX receptors, SREBP2, ROR), G protein-coupled receptor (GPR183), ion channels (NMDA receptors, SLO1), adhesive molecules (α5β1 and ανβ3 integrins), and oxysterol-binding proteins. The diversity of 25-HC-binding proteins points to the ability of HC to affect many physiological and pathological processes. In this review, we focused on the regulation of 25-HC production and its universal role in the control of cellular cholesterol homeostasis, as well as the effects of 25-HC as a signaling molecule mediating the influence of inflammation on the processes in the neuromuscular system and brain. Based on the evidence collected, it can be suggested that 25-HC prevents accumulation of cellular cholesterol and serves as a potent modulator of neuroinflammation, synaptic transmission, and myelinization. An increased production of 25-HC in response to a various type of damage can have a protective role and reduce neuronal loss. At the same time, an excess of 25-HC may exert the neurotoxic effects.

Anthocyanin-rich blackcurrant extract improves long-term memory impairment and emotional abnormality in senescence-accelerated mice.

Alzheimers disease (AD) is associated with a progressive worsening in cognitive function, which is often accompanied by emotional disturbance. Recent studies revealed that anthocyanin-rich blackcurrant extract (BCE) can impart health benefits, but it is not known whether BCE is useful in the prevention andor treatment of AD. Here, we examined the effects of BCE using a senescence-accelerated mouse prone 8 (SAMP8) model. Dietary BCE supplementation for 9 weeks was found to both improve the diminished long-term recognition memory and normalize the anxiety levels of SAMP8 mice. RNA sequencing demonstrated that dietary supplementation with anthocyanin-rich BCE significantly altered the gene expression profile in the hippocampus. According to enrichment analysis, genes regulated by BCE were related to cellular component terms such as smooth endoplasmic reticulum, axon, and glutamatergic synapse. Real-time PCR verified alterations in the expression of AD-related genes. These findings indicate that anthocyanin-rich BCE may be valuable for the prevention andor treatment of AD. PRACTICAL APPLICATIONS Blackcurrant contains an abundance of polyphenols, especially anthocyanins. This study demonstrated that anthocyanin-rich BCE improves the long-term recognition memory impairment and emotional abnormality of SAMP8 mice, a mouse model characterized by several pathological features of AD. These findings indicate that anthocyanin-rich BCE may be a useful food supplement or ingredient for the prevention of AD.

Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL

Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimers disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 6613-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 6613-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROL The online version contains supplementary material available at 10.1186s41120-022-00058-1.

Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers.

Novel plasma biomarkers, especially phosphorylated tau (p-tau), can detect brain tau aggregates in Alzheimer disease. To determine which plasma biomarker combinations can accurately detect tau pathological brain changes in Down syndrome (DS). The cross-sectional, multicenter Alzheimers Biomarker Consortium-Down Syndrome study included adults with DS and a control group of siblings without DS. All participants with plasma, positron emission tomography (PET), and cognitive measures available by the time of data freeze 1.0 were included. Participants were enrolled between 2016 and 2019, and data were analyzed from August 2021 to April 2022. Plasma p-tau217, glial fibrillary acidic protein (GFAP), amyloid β4240 (Aβ42Aβ40), neurofilament light (NfL), and total tau (t-tau) tau positron emission tomography (tau-PET) and Aβ-PET. The primary outcome was tau-PET status. Secondary outcomes included Aβ-PET status and cognitive performance. Among 300 participants with DS and a control group of 37 non-DS siblings, mean (SD) age was 45.0 (10.1) years, and 167 (49.6%) were men. Among participants with DS who all underwent plasma p-tau217 and GFAP analyses, 258 had other plasma biomarker data available and 119, 213, and 288 participants had tau-PET, Aβ-PET, and cognitive assessments, respectively. Plasma p-tau217 and t-tau were significantly increased in Aβ-PET-positive tau-PET-positive (AT) DS and AT- DS compared with A-T- DS while GFAP was only increased in AT DS. Plasma p-tau217 levels were also significantly higher in AT DS than AT- DS. In participants with DS, plasma p-tau217 and GFAP (but not other plasma biomarkers) were consistently associated with abnormal tau-PET and Aβ-PET status in models covaried for age (odds ratio range, 1.59 95% CI, 1.05-2.40 to 2.32 95% CI, 1.36-3.96 P < .03). A combination of p-tau217 and age performed best when detecting tau-PET abnormality in temporal and neocortical regions (area under the curve AUC range, 0.96-0.99). The most parsimonious model for Aβ-PET status included p-tau217, t-tau, and age (AUC range, 0.93-0.95). In multivariable models, higher p-tau217 levels but not other biomarkers were associated with worse performance on DS Mental Status Examination (β, -0.24, 95% CI, -0.36 to -0.12 P < .001) and Cued Recall Test (β, -0.40 95% CI, -0.53 to -0.26 P < .001). Plasma p-tau217 is a very accurate blood-based biomarker of both tau and Aβ pathological brain changes in DS that could help guide screening and enrichment strategies for inclusion of individuals with DS in future AD clinical trials, especially when it is combined with age as a covariate.

An Activity-Based Fluorescent Probe for Imaging Fluctuations of Peroxynitrite (ONOO

Peroxynitrite (ONOO

SORL1 gene mutation and octapeptide repeat insertion in PRNP gene in a case presenting with rapidly progressive dementia and cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) has been associated with a variety of neurodegenerative disorders, included prion diseases and Alzheimers disease its pathophysiology is still largely unknown. We report the case of an 80-year-old man with rapidly progressive dementia and neuroimaging features consistent with CAA carrying two genetic defects in the PRNP and SORL1 genes. Neurological examination, brain magnetic resonance imaging (MRI), electroencephalographic-electromyographic (EEG-EMG) polygraphy, and analysis of 14-3-3 and tau proteins, Aβ40, and Aβ42 in the cerebrospinal fluid (CSF) were performed. The patient underwent a detailed genetic study by next generation sequencing analysis. The patient presented with progressive cognitive dysfunction, generalized myoclonus, and ataxia. Approximately 9 months after symptom onset, he was bed-bound, almost mute, and akinetic. Brain MRI was consistent with CAA. CSF analysis showed high levels of t-tau and p-tau, decreased Aβ42, decreased Aβ42Aβ40 ratio, and absence of 14.3.3 protein. EEG-EMG polygraphy demonstrated diffuse slowing, frontal theta activity, and generalized spike-waves related to upper limb myoclonus induced by intermittent photic stimulation. Genetic tests revealed the presence of the E270K variant in the SORL1 gene and the presence of a single octapeptide repeat insertion in the coding region of the PRNP gene. The specific pathogenic contribution of the two DNA variations is difficult to determine without neuropathology among the possible explanations, we discuss the possibility of their link with CAA. Vascular and degenerative pathways actually interact in a synergistic way, and genetic studies may lead to more insight into pathophysiological mechanisms.

WNTβ-catenin Pathway a Possible Link Between Hypertension and Alzheimers Disease.

Recent research has shown that older people with high blood pressure (BP), or hypertension, are more likely to have biomarkers of Alzheimers disease (AD). Essential hypertension represents the most common cardiovascular disease worldwide and is thought to be responsible for about 13% of all deaths. People with essential hypertension who regularly take prescribed BP medications are half as likely to develop AD as those who do not take them. What then is the connection We know that high BP can damage small blood vessels in the brain, affecting those parts that are responsible for memory and thinking. However, the link between AD and hypertension remains unclear. Recent advances in the field of molecular and cellular biology have revealed a downregulation of the canonical WNTβ-catenin pathway in both hypertension and AD. In AD, the glutamate transport function is decreased, a decrease that is associated with a loss of synapse and neuronal death. β-catenin signaling appears to act as a major regulator of glutamate transporters (EAAT and GS) expression and can be harnessed to remove excess glutamate in AD. This review focuses on the possible link between hypertension and AD through the decreased WNTβ-catenin which interacts with the glutamatergic pathway.