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Challenges in Implementing Futility Schemes, with Reference to Aducanumab.

Stopping an ongoing clinical trial based on an interim analysis that shows poor outcomes, often referred to as a judgment of futility, is a familiar feature in current clinical trials practice. Interim data can be misleading, and the implications of prematurely terminating a trial that should not stop are severe. It is thus critical that designs allowing futility stopping be planned and implemented carefully and cautiously. A recent Phase III development program for aducanumab in Alzheimers disease was halted based on a pre-defined futility guideline, yet based upon updated data and closer examination, the terminated studies became the basis for a regulatory submission. Not surprisingly, this situation generated much controversy and discussion. It provides a good basis for illustrating important principles governing the planning and implementation of futility schemes.

The Role of Iron Metabolism, Lipid Metabolism, and Redox Homeostasis in Alzheimers Disease from the Perspective of Ferroptosis.

In the development of Alzheimers disease (AD), cell death is common. Novel cell death form-ferroptosis is discovered in recent years. Ferroptosis is an iron-regulated programmed cell death mechanism and has been identified in AD clinical samples. Typical characteristics of ferroptosis involve the specific changes in cell morphology, iron-dependent aggregation of reactive oxygen species (ROS) and lipid peroxides, loss of glutathione (GSH), inactivation of glutathione peroxidase 4 (GPX4), and a unique group of regulatory genes. Increasing evidence demonstrates that ferroptosis may be associated with neurological dysfunction in AD. However, the underlying mechanisms have not been fully elucidated. This article reviews the potential role of ferroptosis in AD, the involvement of ferroptosis in the pathological progression of AD through the mechanisms of iron metabolism, lipid metabolism, and redox homeostasis, as well as a range of potential therapies targeting ferroptosis for AD. Intervention strategies based on ferroptosis are promising for Alzheimers disease treatment at present, but further researches are still needed.

Therapeutic potential of blackberry extract in the preventing memory deficits and neurochemical alterations in the cerebral cortex, hippocampus and cerebellum of a rat model with amnesia.

The blackberry (Rubus sp.) is a popular fruit that has a high concentration of phenolic compounds. Pharmacological investigations have demonstrated the important biological activities of the blackberry extract, such as neuroprotective actions. This study aimed to evaluate the effects of blackberry extract on memory and neurochemical parameters in rats subjected to scopolamine (SCO)-induced amnesia. Male rats were divided into five groups I, control (saline) II, SCO III, SCO Rubus sp. (100 mgkg) IV, SCO Rubus sp. (200 mgkg) and V, SCO donepezil (5 mgkg). Blackberry extract and donepezil were orally administered for 10 days. On day 11, group I received saline, and groups II, III, IV, and V received SCO (1 mgkg) intraperitoneally after object recognition behavioral training. Twenty-four hours after the training session, animals were subjected to an object recognition test. Finally, the animals were euthanized, and the cerebral cortex, hippocampus, and cerebellum were collected to evaluate the oxidative stress and acetylcholinesterase (AChE) activity. Rubus sp. extract prevented memory impairment induced by SCO in a manner similar to that of donepezil. Additionally, Rubus sp. extract and donepezil prevented the increase in AChE activity induced by SCO in all the evaluated brain structures. SCO induced oxidative damage in the cerebral cortex, hippocampus, and cerebellum, which was prevented by Rubus sp. and donepezil. Our results suggest that the antioxidant and anticholinesterase activities of Rubus sp. are associated with memory improvement hence, it can potentially be used for the treatment of neurodegenerative diseases.

CEBPβAEP Signaling Drives Alzheimers Disease Pathogenesis.

Alzheimers disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (CEBPβ)asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the CEBPβAEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-CEBPβAEP pathway may serve as a novel therapeutic target for the treatment of AD.

Development and validation of a novel radiomics-clinical model for predicting post-stroke epilepsy after first-ever intracerebral haemorrhage.

Post-stroke epilepsy (PSE) is associated with increased morbidity and mortality. This study aimed to develop and validate a novel prediction model combining clinical factors and radiomics features to accurately identify patients at high risk of developing PSE after intracerebral haemorrhage (ICH). Researchers performed a retrospective medical chart review to extract derivation and validation cohorts of patients with first-ever ICH that attended two tertiary hospitals in China between 2010 and 2020. Clinical data were extracted from electronic medical records and supplemented by tele-interview. Predictive clinical variables were selected by multivariable logistic regression to build the clinical model. Predictive radiomics features were identified, and a Rad-score was calculated according to the coefficient of the selected feature. Both clinical variables and radiomic features were combined to build the radiomics-clinical model. Performances of the clinical, Rad-score, and combined models were compared. A total of 1571 patients were included in the analysis. Cortical involvement, early seizures within 7 days of ICH, NIHSS score, and ICH volume were included in the clinical model. Rad-score, instead of ICH volume, was included in the combined model. The combined model exhibited better discrimination ability and achieved an overall better benefit against threshold probability than the clinical model in the decision curve analysis (DCA). The combined radiomics-clinical model was better able to predict ICH-associated PSE compared to the clinical model. This can help clinicians better predict an individual patients risk of PSE following a first-ever ICH and facilitate earlier PSE diagnosis and treatment. • Radiomics has not been used in predicting the risk of developing PSE. • Higher Rad-scores were associated with higher risk of developing PSE. • The combined model showed better performance of PSE prediction ability.

Immune-mediated platelet depletion augments Alzheimers disease neuropathological hallmarks in APP-PS1 mice.

In Alzheimers disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1 microglia had lower amounts of fibrillar amyloid beta cargo and GFAP astrocytic processes showed a higher overlap with thioflavin S amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.

Familial Alzheimers Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates.

Amyloid-beta (Aβ) deposition as senile plaques is a pathological hallmark of Alzheimers disease (AD). AD is characterized by a large level of heterogeneity in amyloid pathology, whose molecular origin is poorly understood. Here, we employ NMR spectroscopy and MD simulation at ambient and high pressures and investigate how AD-related mutations in Aβ peptide influence the stability of Aβ aggregates. The pressure-induced monomer dissociation from Aβ aggregates monitored by NMR demonstrated that the Iowa (D23N), Arctic (E22G), and Osaka (ΔE22) mutations altered the pressure stability of Aβ40 aggregates in distinct manners. While the NMR data of monomeric Aβ40 showed only small localized effects of mutations, the MD simulation of mutated Aβ fibrils revealed their distinct susceptibility to elevated pressure. Our data propose a structural basis for the distinct stability of various Aβ fibrils and highlights stability as a molecular property potentially contributing to the large heterogeneity of amyloid pathology in AD.

The KEAP1-NRF2 system and neurodegenerative diseases.

Hydroxysafflor yellow A exerts neuroprotective effect by reducing Aβ toxicity through inhibiting endoplasmic reticulum stress in oxygen-glucose deprivationreperfusion cell model.

Ischemia stroke is thought to be one of vascular risks associated with neurodegenerative diseases, such as Alzheimers disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen glucose deprivationreperfusion (OGDR) was used to explore the potential mechanism of HSYA. Results from CCK-8 showed that 10μM HSYA restored the cell viability after OGD 2 hR 24 h. HSYA reduced the levels of malondialdehyde and ROS, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-β peptides (Aβ) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like ER kinase pathway and activating transcription factor 6 pathway, while the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aβ toxicity after OGDR by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving endoplasmic reticulum stress.

LncRNA HOTAIR in exercise-induced neuro-protective function in Alzheimers disease.

Exercise is effective in Alzheimers disease (AD), which is characterized by neuro-degenerative progress with increasing morbidity. The present study aimed to explore whether HOTAIR participated in the regulation of exercise in AD. A relative expression of serum HOTAIR was detected using quantitative real-time polymerase chain reaction (PCR). The diagnostic significance of HOTAIR on distinguishing AD patients was evaluated by receiver operating characteristic (ROC) curve. Correlations between HOTAIR expression and Mini-Mental State Examination (MMSE) score or Alzheimers Disease Assessment Scale-Cognitive (ADAS-Cog) score were analyzed with Pearsons test. Logistic regression analysis was applied to investigate factors as independent indicators for HOTAIR expression. In AD patients, the expression of HOTAIR was increased, and it could function as a diagnostic marker in AD patients. The expression of HOTAIR was associated with MMSE score and ADAS-Cog score in AD patients before exercise. Exercise ameliorated the cognitive impairment and reduced the relative serum expression of HOTAIR. Exercise was proved to be an independent indicator of HOTAIR expression. HOTAIR was a possible biomarker for indicating AD patients, and it was correlated with MMSE scores and ADAS-Cog results. Exercise might moderate AD progress via controlling HOTAIR.

Modelling the contributions to hyperexcitability in a mouse model of Alzheimers disease.

Neuronal hyperexcitability is a pathological characteristic of Alzheimers disease (AD). Three main mechanisms have been proposed to explain it i), dendritic degeneration leading to in-creased input resistance, ii), ion channel changes leading to enhanced intrinsic excitability, and iii), synaptic changes leading to excitation-inhibition (EI) imbalance. However, the relative contribution of these mechanisms is not fully understood. Therefore, we performed biophysi-cally realistic multi-compartmental modelling of neuronal excitability in reconstructed CA1 pyramidal neurons from wild-type and APPPS1 mice, a well-established animal model of AD. We show that, for synaptic activation, the excitability promoting effects of dendritic degen-eration are cancelled out by decreased excitation due to synaptic loss. We find an interesting balance between excitability regulation and an enhanced degeneration in the basal dendrites of APPPS1 cells, potentially leading to increased excitation by the apical but decreased excitation by the basal Schaffer collateral pathway. Furthermore, our simulations reveal three pathomechanistic scenarios that can account for the experimentally observed increase in firing and bursting of CA1 pyramidal neurons in APPPS1 mice. Scenario 1 enhanced EI ratio Scenario 2 alteration of intrinsic ion channels (I

The molecular mechanism of γ-aminobutyric acid against AD the role of CEBPαcircAPLP2miR-671-5p in regulating CNTN12 expression.

The expression levels of the synaptic-related proteins contactin 12 (CNTN12) are down-regulated in the brain of Alzheimers disease (AD), but the mechanism has not been clarified. γ-Aminobutyric acid (GABA) is considered a biologically active ingredient in food. Our previous research revealed that GABA can regulate CEBPα expression in Aβ-treated U251 cells. However, it is uncertain whether GABA can antagonize the pathogenesis of AD. Whether GABA can inhibit the reduction in CNTN12 expression by regulating CEBPαcircAPLP2miR-671-5p in the AD brain remains unclear yet. Here, we demonstrate that GABA could attenuate the deposition of Aβ in the brain and ameliorate cognitive impairments in AD model mice. The expressions of CEBPα, circAPLP2, and CNTN12 were decreased and that of miR-671-5p was increased in AD model mouse brains and Aβ-induced SH-SY5Y cells. These alterations were partly reversed by GABA. The CNTN12 expression was down-regulated and up-regulated in SH-SY5Y cells treated with miR-671-5p mimics and miR-671-5p inhibitors, respectively. The results from the luciferase reporter assay revealed that miR-671-5p could bind to the 3-untranslated region of circAPLP2. The silencing of circAPLP2 with the siRNA duplex caused an up-regulation of miR-671-5p and a down-regulation of CNTN12 in SH-SY5Y cells. The silencing of CEBPα with the siRNA duplex caused a down-regulation of circAPLP2 or CNTN12 and an up-regulation of miR-671-5p. In conclusion, GABA may decrease the deposition of Aβ in the brain, inhibit the down-regulation of CNTN12 expression, and ameliorate the cognitive deficits of AD model mice. The CEBPαcircAPLP2miR-671-5p pathway plays a role in regulating CNTN12 expression by GABA in AD.

Discriminative accuracy of the ATN scheme to identify cognitive impairment due to Alzheimers disease.

The optimal combination of amyloid-βtauneurodegeneration (ATN) biomarker profiles for the diagnosis of Alzheimers disease (AD) dementia is unclear. We examined the discriminative accuracy of ATN combinations assessed with neuroimaging biomarkers for the differentiation of AD from cognitively unimpaired (CU) elderly and non-AD neurodegenerative diseases in the TRIAD, BioFINDER-1 and BioFINDER-2 cohorts (total For the diagnosis of AD dementia (vs. CU elderly), T biomarkers performed as well as the complete ATN system (AUC range 0.90-0.99). A and T biomarkers in isolation performed as well as the complete ATN system in differentiating AD dementia from non-AD neurodegenerative diseases (AUC range A biomarker 0.84-1 T biomarker 0.83-1). In diagnostic settings, the use of A or T neuroimaging biomarkers alone can reduce patient burden and medical costs compared with using their combination, without significantly compromising accuracy.

Bringing to light the physiological and pathological firing patterns of human induced pluripotent stem cell-derived neurons using optical recordings.

Human induced pluripotent stem cells (hiPSCs) are a promising approach to study neurological and neuropsychiatric diseases. Most methods to record the activity of these cells have major drawbacks as they are invasive or they do not allow single cell resolution. Genetically encoded voltage indicators (GEVIs) open the path to high throughput visualization of undisturbed neuronal activity. However, conventional GEVIs perturb membrane integrity through inserting multiple copies of transmembrane domains into the plasma membrane. To circumvent large add-ons to the plasma membrane, we used a minimally invasive novel hybrid dark quencher GEVI to record the physiological and pathological firing patterns of hiPSCs-derived sensory neurons from patients with inherited erythromelalgia, a chronic pain condition associated with recurrent attacks of redness and swelling in the distal extremities. We observed considerable differences in action potential firing patterns between patient and control neurons that were previously overlooked with other recording methods. Our system also performed well in hiPSC-derived forebrain neurons where it detected spontaneous synchronous bursting behavior, thus opening the path to future applications in other cell types and disease models including Parkinsons disease, Alzheimers disease, epilepsy, and schizophrenia, conditions associated with disturbances of neuronal activity and synchrony.

Alzheimers disease biomarkers in patients with obstructive sleep apnea hypopnea syndrome and effects of surgery A prospective cohort study.

Obstructive sleep apnea hypopnea syndrome (OSAHS) may cause Alzheimers disease (AD), t-tau, p-tau, Aβ42, and Aβ40 are important elements in the process of AD, and changes in the levels of these biomarkers may affect the cognitive functioning of patients. Our objective was to investigate whether uvulopalatopharyngoplasty could reduce the plasma levels of AD biomarkers in OSAHS patients and the potential correlations of AD biomarkers with cognitive impairment and sleepiness, and explore the independent influencing factors of cognitive function. Alzheimers disease biomarkers were measured in the plasma of 35 patients with severe OSAHS requiring surgical treatment and 16 healthy controls without OSAHS. The cognitive function and sleepiness of OSAHS patients was also evaluated. The case group was given uvulopalatopharyngoplasty and followed at the postoperative sixth month, the follow-up cases were 27, and plasma AD biomarker levels, cognitive function, and sleepiness were re-evaluated. The preoperative and postoperative AD biomarker levels OSAHS patients were compared with each other and those of the control group. Linear stepwise regression and lasso regression were used to explore the relationships of AD biomarkers with cognitive impairment and sleepiness. Significantly higher Aβ40, t-tau, p-tau in plasma were observed preoperatively in OSAHS patients comparing to controls (29.24 ± 32.52 vs. 13.18 ± 10.78, Obstructive sleep apnea hypopnea syndrome can increase plasma AD biomarkers levels. Uvulopalatopharyngoplasty can improve patients cognition and sleepiness, and the mechanism may be related to changes in plasma AD biomarkers. Higher AHI and higher t-tau level were identified as independent risk factors for cognitive decline.

An analysis of neurovascular disease markers in the hippocampus of

It is considered that Three age groups of A significant difference was observed between the 15-day group and the other two age groups, where as there were no significant differences between the 3-month and 1.5-year age groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that differentially expressed proteins could be enriched in several pathways related to neurovascular diseases, such as metabolic pathways for Alzheimers disease (AD), Huntingtons disease, Parkinsons disease, and other diseases. The KEGG enrichment also showed that relevant protein involved in oxidative phosphorylation in the hippocampus of It was suggested that when the hippocampus of

High-fiber-diet-related metabolites improve neurodegenerative symptoms in patients with obesity with diabetes mellitus by modulating the hippocampal-hypothalamic endocrine axis.

Through transcriptomic and metabolomic analyses, this study examined the role of high-fiber diet in obesity complicated by diabetes and neurodegenerative symptoms. The expression matrix of high-fiber-diet-related metabolites, blood methylation profile associated with pre-symptomatic dementia in elderly patients with type 2 diabetes mellitus (T2DM), and high-throughput single-cell sequencing data of hippocampal samples from patients with Alzheimers disease (AD) were retrieved from the Gene Expression Omnibus (GEO) database and through a literature search. Data were analyzed using principal component analysis (PCA) after quality control and data filtering to identify different cell clusters and candidate markers. A protein-protein interaction network was mapped using the STRING database. To further investigate the interaction among high-fiber-diet-related metabolites, methylation-related DEGs related to T2DM, and single-cell marker genes related to AD, AutoDock was used for semi-flexible molecular docking. Based on GEO database data and previous studies, 24 marker genes associated with high-fiber diet, T2DM, and AD were identified. Top 10 core genes include SYNE1, ANK2, SPEG, PDZD2, KALRN, PTPRM, PTPRK, BIN1, DOCK9, and NPNT, and their functions are primarily related to autophagy. According to molecular docking analysis, acetamidobenzoic acid, the most substantially altered metabolic marker associated with a high-fiber diet, had the strongest binding affinity for SPEG. By targeting the SPEG protein in the hippocampus, acetamidobenzoic acid, a metabolite associated with high-fiber diet, may improve diabetic and neurodegenerative diseases in obese people.

Integration of amyloid-β oligomerization tendency as a plasma biomarker in Alzheimers disease diagnosis.

There has been significant development in blood-based biomarkers targeting amyloidopathy of Alzheimers disease (AD). However, the guidelines for integrating such biomarkers into AD diagnosis are still inadequate. Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) as a plasma biomarker detecting oligomerization tendency is available in the clinical practice. We suggest how to interpret the results of plasma biomarker for amyloidopathy using MDS-OAβ with neuropsychological test, brain magnetic resonance imaging (MRI), and amyloid PET for AD diagnosis. Combination of each test result differentiates various stages of AD, other neurodegenerative diseases, or cognitive impairment due to the causes other than neurodegeneration. A systematic interpretation strategy could support accurate diagnosis and staging of AD. Moreover, comprehensive use of biomarkers that target amyloidopathy such as amyloid PET on brain amyloid plaque and MDS-OAβ on amyloid-β oligomerization tendency can complement to gain advanced insights on amyloid-β dynamics in AD.

Identification of immune signatures in Parkinsons disease based on co-expression networks.

Parkinsons disease (PD) is a common neurodegenerative disease in middle-aged and elderly people, and there is less research on the relationship between immunity and PD. In this study, the protein-protein interaction networks (PPI) data, 2747 human immune-related genes (HIRGs), 2078 PD-related genes (PDRGs), and PD-related datasets (GSE49036 and GSE20292) were downloaded from the Human Protein Reference Database (HPRD), Amigo 2, DisGeNET, and Gene Expression Omnibus (GEO) databases, respectively. An immune- or PD-directed neighbor co-expressed network construction (IOPDNC) was drawn based on the GSE49036 dataset and HPRD database. Furthermore, a PD-directed neighbor co-expressed network was constructed. Modular clustering analysis was performed on the genes of the gene interaction network obtained in the first step to obtain the central core genes using the GraphWeb online website. The modules with the top 5 functional scores and the number of core genes greater than six were selected as PD-related gene modules. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of different module genes were performed. The single sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to calculate the immune cell infiltration of the PD and the normal samples. The quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was performed to investigate the expression of module genes. An IOPDNC and PD-directed neighbor co-expressed network (PDNC network) were constructed. Furthermore, a total of 5 immune-PD modules were identified which could distinguish between PD and normal samples, and these module genes were strongly related to PD in protein interaction level or gene expression level. In addition, functional analysis indicated that module genes were involved in various neurodegenerative diseases, such as Alzheimer disease, Huntington disease, Parkinson disease, and Long-term depression. In addition, the genes of the 6 modules were significantly associated with these 4 differential immune cells (aDC cells, eosinophils, neutrophils, and Th2 cells). Finally, the result of qRT-PCR manifested that the expression of 6 module genes was significantly higher in normal samples than in PD samples. In our study, the immune-related genes were found to be strongly related to PD and might play key roles in PD.

Cardiorespiratory fitness levels and body mass index of pre-adolescent children and older adults during the COVID-19 pandemic.

The social and behavioral effects of the COVID-19 pandemic have impacted the health and physiology of most people, including those never diagnosed with COVID-19. While the impact of the pandemic has been felt across the lifespan, its effects on cardiorespiratory fitness (commonly considered a reflection of total body health) of older adults and children may be particularly profound due to social distancing and stay-at-home advisories, as well as the closure of sport facilities and non-essential businesses. The objective of this investigation was to leverage baseline data from two ongoing clinical trials to determine if cardiorespiratory fitness and body mass index were different during COVID-19 relative to before COVID-19 in older adults and children. Healthy older individuals ( Results revealed that older adults and children tested during COVID-19 had significantly lower cardiorespiratory fitness levels than those tested before COVID-19 shutdowns (older adults 30% lower children 53% lower Results from this investigation indicate that the COVID-19 pandemic, and behavior changes taken to reduce potential exposure, may have led to lower cardiorespiratory fitness levels in older adults and children, as well as higher body mass index. These findings provide relevant public health information as lower cardiorespiratory fitness levels and higher body mass indexes recorded during the pandemic could have far-reaching and protracted health consequences. Public health guidance is needed to encourage physical activity to maintain cardiorespiratory fitness and healthy body composition. Older adults httpsclinicaltrials.govct2showNCT02875301, identifier NCT02875301 Children httpsclinicaltrials.govct2showNCT03592238, identifier NCT03592238.

APOE4 A Culprit for the Vulnerability of COVID-19 in Alzheimers Patients.

Apolipoprotein E4 (APOE4) is one of the primary genetic risk factors for late-onset of Alzheimers disease (AD). While its primary function is to transport cholesterol, it also regulates metabolism, aggregation, and deposition of amyloid-β (Aβ) in the brain. The disruption in the generation and removal of Aβ in the brain is the primary cause of memory and cognitive loss and thus plays a significant role in the development of AD. In several prior genetic investigations, the APOE4 allele has been linked to higher susceptibility to severe acute respiratory syndrome (SARS-CoV-2) infection and COVID-19 mortality. However, information on the involvement of APOE4 in the underlying pathology and clinical symptoms is limited. Due to the high infection and mortality rate of COVID-19 in AD individuals, challenges have been identified in the management of AD patients during the COVID-19 pandemic. In order to provide evidence-based, more effective healthcare, it is critical to identify underlying concerns and, preferably, biomarkers. The risk variant APOE4 imparts enhanced infectivity by the underlying coronavirus SARS-CoV-2 at a cellular level, genetic level, and route level. Here we review existing advances in clinical and basic research on the AD-related gene APOE, as well as the role of APOE in AD pathogenesis, using neurobiological evidence. Moreover, the role of APOE in severe COVID-19 in Alzheimers patients has also been reviewed.

Recruitment across two decades of NIH-funded Alzheimers disease clinical trials.

Timely accrual of a representative sample is a key factor in whether Alzheimers disease (AD) clinical trials successfully answer the scientific questions under study. Studies in other fields have observed that, over time, recruitment to trials has become increasingly reliant on larger numbers of sites, with declines in the average per-site recruitment rate. Here, we examined the trends in recruitment over a 20-year period of NIH-funded AD clinical trials conducted by the Alzheimers Disease Cooperative Study (ADCS), a temporally consistent network of sites devoted to interventional research. We performed retrospective analyses of eleven ADCS randomized clinical trials. To examine the recruitment planning, we calculated the expected number of participants to be enrolled per site for each trial. To examine the actual trial recruitment rates, we quantified the number of participants enrolled per site per month. No effects of time were observed on recruitment planning or overall recruitment rates across trials. No trial achieved an overall recruitment rate greater than one subject per site per month. We observed the fastest recruitment rates in trials with no competition and the slowest in trials that overlapped in time. The highest recruitment rates were consistently seen early within trials and declined over the course of studies. Trial recruitment projections should plan for fewer than one participant randomized per site per month and consider the number of other AD trials being conducted concurrently.

Common mouse models of tauopathy reflect early but not late human disease.

Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimers Disease (AD) and while several drugs showed therapeutic effects in these mice, they were ineffective in humans. This leads to the question to which extent the murine models reflect human Tau pathology on the molecular level. We isolated insoluble, aggregated Tau species from two common AD mouse models during different stages of disease and characterized the modification landscape of the aggregated Tau using targeted and untargeted mass spectrometry-based proteomics. The results were compared to human AD and to human patients that suffered from early onset dementia and that carry the P301L Tau mutation. Both mouse models accumulate insoluble Tau species during disease. The Tau aggregation is driven by progressive phosphorylation within the proline rich domain and the C-terminus of the protein. This is reflective of early disease stages of human AD and of the pathology of dementia patients carrying the P301L Tau mutation. However, Tau ubiquitination and acetylation, which are important to late-stage human AD are not represented in the mouse models. AD mouse models that overexpress human Tau using risk mutations are a suitable tool for testing drug candidates that aim to intervene in the early formation of insoluble Tau species promoted by increased phosphorylation of Tau.

Hippocampus-centred grey matter covariance networks predict the development and reversion of mild cognitive impairment.

Mild cognitive impairment (MCI) has been thought of as the transitional stage between normal ageing and Alzheimers disease, involving substantial changes in brain grey matter structures. As most previous studies have focused on single regions (e.g. the hippocampus) and their changes during MCI development and reversion, the relationship between grey matter covariance among distributed brain regions and clinical development and reversion of MCI remains unclear. With samples from two independent studies (155 from the Beijing Aging Brain Rejuvenation Initiative and 286 from the Alzheimers Disease Neuroimaging Initiative), grey matter covariance of default, frontoparietal, and hippocampal networks were identified by seed-based partial least square analyses, and random forest models were applied to predict the progression from normal cognition to MCI (N-t-M) and the reversion from MCI to normal cognition (M-t-N). With varying degrees, the grey matter covariance in the three networks could predict N-t-M progression (AUC 0.692-0.792) and M-t-N reversion (AUC 0.701-0.809). Further analyses indicated that the hippocampus has emerged as an important region in reversion prediction within all three brain networks, and even though the hippocampus itself could predict the clinical reversion of M-t-N, the grey matter covariance showed higher prediction accuracy for early progression of N-t-M. Our findings are the first to report grey matter covariance changes in MCI development and reversion and highlight the necessity of including grey matter covariance changes along with hippocampal degeneration in the early detection of MCI and Alzheimers disease.

TNEA therapy promotes the autophagic degradation of NLRP3 inflammasome in a transgenic mouse model of Alzheimers disease via TFEBTFE3 activation.

The impairment in the autophagy-lysosomal pathway (ALP) and the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome represent two molecular events leading to neurodegeneration and neuroinflammation in Alzheimers disease (AD), a devastating neurodegenerative disorder without a cure. Previously we demonstrated the cognitive-enhancing effect of a combined electroacupuncture (EA) therapy termed TNEA in a transgenic mouse model of AD, involving activation of transcription factor EB (TFEB), a master regulator of ALP. However, whether and how TNEA inhibits NLRP3 inflammasome via TFEB-mediated ALP in AD remains to be investigated. 5xFAD mice overexpressing amyloid-β (Aβ) were treated with TNEA or EA on its composing acupoints (GB13 and GV24). The changes in the signaling pathways regulating NLRP3 inflammasome, the association of NLRP3 inflammasome with ALP, and the roles of TFEBTFE3 in mice brains were determined by immunoblots, immunohistochemistry and AAV-mediated knockdown assays. TNEA inhibits the activation of NLRP3 inflammasome and the release of active interleukin 1β (IL1B) in the hippocampi of 5xFAD mice. Mechanistically, TNEA promoted the autophagic degradation of inflammasome components via activating both TFEB and TFE3 by modulating kinases including AMPK and AKT. The composing acupoints in TNEA showed synergistic effects on regulating these molecular events and memory improvement. Our findings suggest that TNEA attenuates AD-associated memory impairment via promoting TFEBTFE3-mediated autophagic clearance of Aβ and NLRP3 inflammasome, and partially reveal the molecular basis of combined acupoints therapy originated from ancient wisdom.

Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimers disease.

Complex diseases are characterized by spatiotemporal cellular and molecular changes that may be difficult to comprehensively capture. However, understanding the spatiotemporal dynamics underlying pathology can shed light on disease mechanisms and progression. Here we introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection in the same tissue section. As proof of principle, we analyze brain tissues of a mouse model of Alzheimers disease at 8 and 13 months of age. Our approach provides a comprehensive cellular map of disease progression. It reveals a core-shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocyte-like (DAA-like) cells and oligodendrocyte precursor cells (OPCs) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerges mainly in excitatory neurons in the CA1 region and correlates with the local enrichment of oligodendrocyte subtypes. The STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing a tool to pinpoint the molecular and cellular changes underlying pathology.

Age, sex, and apolipoprotein E isoform alter contextual fear learning, neuronal activation, and baseline DNA damage in the hippocampus.

Age, female sex, and apolipoprotein E4 (E4) are risk factors to develop Alzheimers disease (AD). There are three major human apoE isoforms E2, E3, and E4. Compared to E3, E4 increases while E2 decreases AD risk. However, E2 is associated with increased risk and severity of post-traumatic stress disorder (PTSD). In cognitively healthy adults, E4 carriers have greater brain activation during learning and memory tasks in the absence of behavioral differences. Human apoE targeted replacement (TR) mice display differences in fear extinction that parallel human data E2 mice show impaired extinction, mirroring heightened PTSD symptoms in E2 combat veterans. Recently, an adaptive role of DNA double strand breaks (DSBs) in immediate early gene expression (IEG) has been described. Age and disease synergistically increase DNA damage and decrease DNA repair. As the mechanisms underlying the relative risks of apoE, sex, and their interactions in aging are unclear, we used young (3 months) and middle-aged (12 months) male and female TR mice to investigate the influence of these factors on DSBs and IEGs at baseline and following contextual fear conditioning. We assessed brain-wide changes in neural activation following fear conditioning using whole-brain cFos imaging in young female TR mice. E4 mice froze more during fear conditioning and had lower cFos immunoreactivity across regions important for somatosensation and contextual encoding compared to E2 mice. E4 mice also showed altered co-activation compared to E3 mice, corresponding to human MRI and cognitive data, and indicating that there are differences in brain activity and connectivity at young ages independent of fear learning. There were increased DSB markers in middle-aged animals and alterations to cFos levels dependent on sex and isoform, as well. The increase in hippocampal DSB markers in middle-aged animals and female E4 mice may play a role in the risk for developing AD.

Distinct spatiotemporal subtypes of amyloid deposition are associated with diverging disease profiles in cognitively normal and mild cognitive impairment individuals.

We aimed to investigate the relationship between spatiotemporal changes of amyloid deposition and Alzheimers disease (AD) profiles in cognitively normal (CN) and those with mild cognitive impairment (MCI). Using a data-driven method and amyloid-PET data, we identified and validated two subtypes in two independent datasets (discovery dataset N 548, age 72.4 ± 6.78, 49% female validation dataset N 348, age 74.9 ± 8.16, 47% female) from the Alzheimers Disease Neuroimaging Initiative across a range of individuals who were CN or had MCI. The two subtypes showed distinct regional progression patterns and presented distinct genetic, clinical and biomarker characteristics. The cortex-priority subtype was more likely to show typical clinical syndromes of symptomatic AD and vice versa. Furthermore, the regional progression patterns were associated with clinical and biomarker profiles. In sum, our findings suggest that the spatiotemporal variants of amyloid depositions are in close association with disease trajectories these findings may provide insight into the disease monitoring and enrollment of therapeutic trials in AD.

The AAA chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system.

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimers disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.

Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.

Alzheimers disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tauRNA interactions remain limited. Here we employ molecular interaction studies to measure the impact of tauRNA binding on tau microtubule binding and aggregation. To investigate the importance of tauRNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (mAb TRC35) against aggregated tauRNA complexes. Here we show native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau mediated microtubule assembly functions. TauRNA interaction in vitro promotes the formation of higher molecular weight tauRNA complexes which represent an oligomeric tau species. Co-expression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimers disease-derived detergent insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimers disease, progressive supranuclear palsy, corticobasal degeneration, and Picks disease. We also identify ocular pharyngeal muscular dystrophy as a novel tauopathy disorder where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from postmortem human brain. TauRNA binding drives tau conformational change and aggregation inhibiting tau mediated microtubule assembly. Our findings implicate cellular tauRNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders, and suggest feasibility for novel therapeutic approaches targeting TRCs.

TEMPORAL IRREVERSIBILITY OF LARGE-SCALE BRAIN DYNAMICS IN ALZHEIMERS DISEASE.

Healthy brain dynamics can be understood as the emergence of a complex system far from thermodynamic equilibrium. Brain dynamics are temporally irreversible and thus establish a preferred direction in time (i.e., arrow of time). However, little is known about how the time-reversal symmetry of spontaneous brain activity is affected by Alzheimers disease (AD). We hypothesized that the level of irreversibility would be compromised in AD, signaling a fundamental shift in the collective properties of brain activity towards equilibrium dynamics. We investigated the irreversibility from resting-state fMRI and EEG data in male and female human patients with AD and elderly healthy control subjects (HC). We quantified the level of irreversibility and, thus, proximity to non-equilibrium dynamics by comparing forward and backward timeseries through time-shifted correlations. AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels and at multiple oscillatory frequency bands. At the local level, temporoparietal and frontal regions were affected by AD. The limbic, frontoparietal, default mode, and salience networks were the most compromised at the network level. The temporal reversibility was associated with cognitive decline in AD and grey matter volume in HC. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from controls. Findings were validated using an out-of-sample cohort. Present results offer new evidence regarding pathophysiological links between the entropy generation rate of brain dynamics and the clinical presentation of AD, opening new avenues for dementia characterization at different levels.

Insulin decreases epileptiform activity in rat layer 56 prefrontal cortex in vitro.

Accumulating evidence indicates that insulin-mediated signaling in the brain may play important roles in regulating neuronal function. Alterations to insulin signaling are associated with the development of neurological disorders including Alzheimers disease and Parkinsons disease. Also, hyperglycemia and insulin resistance have been associated with seizure activity and brain injury. In recent work, we found that insulin increased inhibitory GABA

Reduced endothelial caveolin-1 underlies deficits in brain insulin signalling in type 2 diabetes.

Patients with type 2 diabetes exhibit severe impairments in insulin signaling in the brain and are 5-times more likely to develop Alzheimers disease. However, what leads to these impairments is not fully understood. Here, we show reduced expression of endothelial cell caveolin-1 (Cav-1) in the dbdb (Leprdb) mouse model of type-2 diabetes. This reduction correlated with alterations in insulin receptor expression and signaling in brain microvessels as well as brain parenchyma. These findings were recapitulated in the brains of endothelial cell-specific Cav-1 knock-out (Tie2Cre Cav-1flfl) mice. Lack of Cav-1 in endothelial cells led to reduced response to insulin as well as reduced insulin uptake. Furthermore, we observed that Cav-1 was necessary for the stabilization of insulin receptors in lipid rafts. Interactome analysis revealed the insulin receptor interacts with Cav-1 and caveolae-associated proteins, insulin degrading enzyme, and the tight junction protein Zonula Occludence-1 in brain endothelial cells. Restoration of Cav-1 in Cav-1 knockout brain endothelial cells rescued insulin receptor expression and localization. Overall, these results suggest that Cav-1 regulates insulin signaling and uptake by brain endothelial cells by regulating IR-a and IR-b localization and function in lipid rafts. Furthermore, depletion of endothelial cell specific Cav-1 and the resulting impairment in insulin transport leads to alteration in insulin signaling in the brain parenchyma of type 2 diabetes.

Clinical efficacy and safety of compound Congrong Yizhi Capsules on Alzheimers disease in mainland China A systematic review with trial sequential analysis and GRADE assessment.

Alzheimers disease (AD) is a degenerative disease of the central nervous system (CNS) with insidious onset. AD is also the most common cause of dementia. Compound Congrong Yizhi Capsules (CCYC), a traditional Chinese medicine compound developed by the team of Beijing University of Chinese Medicine, has been widely used to treat AD. To systematically evaluate the clinical efficacy and safety of CCYC for AD by meta-analysis, Trial Sequential Analysis (TSA) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This study was registered at PROSPERO (CRD42022295496). Randomized controlled trials (RCTs) of CCYC as the treatment for AD published before December 1, 2021 were retrieved from 4 Chinses databases, 4 English databases and 2 clinical trials registration systems. RevMan 5.4 and STATA 17.0 was used to conduct the meta-analysis of the included studies, the quality of outcomes was rated by the GRADE system, the TSA was conducted by TSA 0.9.5.10 software. Seven studies were included, and the total sample size was 746. Meta-analysis showed that 6 months of treatment with CCYC plus conventional Western medicine treatments (CTs) improved MMSE scores compared with CTs alone (WMD 4.32, 95% CI 3.23, 5.42), and TSA confirmed that more trials in the future will not reverse the result. Among which, CCYC combined with donepezil can significantly improve MMSE scores (WMD 3.54, 95% CI 2.86, 4.22). CCYC combined with olanzapine also showed good effect on both MMSE (WMD 6.49, 95% CI 5.54, 7.44) and ADL scores (WMD 5.23, 95% CI 4.63, 5.83). No serious adverse events were reported. The strengths of the evidences above are MODERATE. CCYC combined with cognition-modifying Western medicine can improve cognitive function, mental behavioural symptoms, and activities of daily living in AD patients with good safety.

In-depth investigation of the mechanisms of Schisandra chinensis polysaccharide mitigating Alzheimers disease rat via gut microbiota and feces metabolomics.

Schisandra chinensis (S. chinensis) is an herbal medicine used for the treatment of Alzheimers disease (AD). The purified polysaccharide fraction, namely SCP2, was previously isolated from S. chinensis crude polysaccharide (SCP) and its structure and in vitro activity were investigated. However, the in vivo activity of SCP2 and its potential mechanism for the treatment of AD have yet to be determined. This study used a combination of microbiomics and metabolomics to comprehensively explore the microbiota and metabolic changes in AD rats under SCP2 intervention, with the aim of elucidating the potential mechanisms of SCP2 in the treatment of AD. SCP2 showed significant therapeutic effects in AD rats, as evidenced by improved learning and memory capacity, reduced neuroinflammation, and restoration of the integrity of the intestinal barrier. Fecal metabolomic and microbiomic analyses revealed that SCP2 significantly modulated 19 endogenous metabolites and reversed gut microbiota disorders in AD rats. Moreover, SCP2 significantly increased the content of short-chain fatty acid (SCFAs) in the AD rats. Correlation analysis showed a significant correlation between gut microbes, metabolites and the content of SCFAs. Collectively, these findings will provide the basis for further development of SCP2.

Integrate transcriptomic and metabolomic analysis reveals the underlying mechanisms of behavioral disorders in zebrafish (Danio rerio) induced by imidacloprid.

Imidacloprid, a widely used neonicotinoid insecticide, poses a significant threat to aquatic ecosystems. Behavior is a functional indicator of the net sensory, motor, and integrative processes of the nervous system and is presumed to be more sensitive in detecting toxicity. In the present study, we investigated the behavioral effects of imidacloprid at the level of environmental concentrations (1, 10 and 100 μgL) for a constant exposure to zebrafish adults, and performed the integrated transcriptomic and metabolomic analysis to analyze the molecular mechanism underlying behavioral effects of imidacloprid. Our results show that imidacloprid exposure significantly induce behavioral disruptions characterized by anxiety, depression, and reduced physiological function including exploratory, decision, social interaction and locomotor activity. Integrated transcriptomic and metabolomic analysis indicate that the disruption of circadian rhythm, metabolic imbalance of arginine and proline, and neurotransmitter disorder are the underlying molecular mechanisms of behavioral impairment induced by imidacloprid. The gene-metabolite-disease network consisted by 11 metabolites and 15 genes is associated human disease Alzheimers disease (AD) and schizophrenia. Our results confirm the behavioral impairment induced by imidacloprid at environmental concentrations for constant exposure. The identified genes and metabolites can be used not only to illustrate the underlying mechanisms, but also can be developed as biomarkers in determining the ecological risk of imidacloprid to aquatic organisms even Homo sapiens.

A cellular taxonomy of the adult human spinal cord.

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding of spinal cellular diversity, characterizing human biology directly is important to uncover specialized features of basic function and human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single-nucleus RNA sequencing with spatial transcriptomics and antibody validation. We identified 29 glial clusters and 35 neuronal clusters, organized principally by anatomical location. To demonstrate the relevance of this resource to human disease, we analyzed spinal motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) and other diseases. We found that compared with other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, suggesting a specialized molecular repertoire underlying their selective vulnerability. We include a web resource to facilitate further investigations into human spinal cord biology.

DNA Aβ42 immunization via needle-less Jet injection in mice and rabbits as potential immunotherapy for Alzheimers disease.

Alzheimers disease (AD) is the most common form of dementia found in the elderly and disease progression is associated with accumulation of Amyloid beta 1-42 (Aβ42) in brain. An immune-mediated approach as a preventive intervention to reduce amyloid plaques without causing brain inflammation is highly desirable for future clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aβ42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and thus differs quantitatively and qualitatively from immune responses elicited by peptides, which are inflammatory with production of IFNγ and IL-17 cytokines by activated T cells. DNA immunization has historically been proven difficult to apply to larger mammals. A potential barrier to use DNA immunization in large mammals is the method for delivery of the DNA antigen. We tested jet injection in mice and rabbits and found good antibody production and safe immune responses (no inflammatory cytokines). We found significant reduction of amyloid plaques and Aβ peptides in brains of the DNA Aβ42 immunized 3xTg-AD mouse model. This study was designed to optimize DNA delivery for possible testing of the DNA Aβ42 vaccine for AD prevention in a clinical trial.

Recent advances on bioactive compounds, biosynthesis mechanism, and physiological functions of Nelumbo nucifera.

Nelumbo nucifera Gaertn, commonly known as lotus, is a genus comprising perennial and rhizomatous aquatic plants, found throughout Asia and Australia. This review aimed to cover the biosynthesis of flavonoids, alkaloids, and lipids in plants and their types in different parts of lotus. This review also examined the physiological functions of bioactive compounds in lotus and the extracts from different organs of the lotus plant. The structures and identities of flavonoids, alkaloids, and lipids in different parts of lotus as well as their biosynthesis were illustrated and updated. In the traditional medicine systems and previous scientific studies, bioactive compounds and the extracts of lotus have been applied for treating inflammation, cancer, liver disease, Alzheimers disease, etc. We suggest future studies to be focused on standardization of the extract of lotus, and their pharmacological mechanisms as drugs or functional foods. This review is important for the lotus-based food processing and application.

Transitions Experiences of younger persons recently diagnosed with Alzheimer-type dementia.

Receiving a diagnosis of dementia before the age of 65 has a huge impact on everyday life. Previously, the disease trajectory has mainly been described from the perspective of older persons. However, young persons with dementia are confronted with specific challenges, influencing the type of life-changing events, or critical points that they may experience. The aim of this study was therefore to describe experiences of persons recently being diagnosed with young-onset dementia. In total, 14 participants with dementia due to Alzheimers disease (10 woman4 men) with an average age of 59 were included in the study. Interviews were conducted within 2 months after receiving the diagnosis and analyzed using qualitative content analysis with an inductive approach, resulting in three categories (1)

DUSP15 expression is reduced in the hippocampus of Myrf knock-out mice but attention and object recognition memory remain intact.

The atypical protein tyrosine phosphatase enzyme, dual-specificity phosphate 15 (DUSP15) is thought to be activated by myelin regulatory factor (MyRF) and to have a role in oligodendrocyte differentiation. Here, we assess whether Dusp15 is reduced in the hippocampus of mice with conditional knock-out of Myrf in oligodendrocyte precursor cells. Using quantitative polymerase chain reaction (qPCR) we found that Dusp15 expression was indeed lower in these mice. Alterations in myelin have been associated with Alzheimers disease (AD), autism spectrum disorder (ASD) and attention deficithyperactivity disorder (ADHD). Symptoms of these disorders can include impairments of object recognition and attention. We, therefore tested the mice in the object recognition task (ORT) and 5-choice serial reaction time task (5CSRTT). However, we did not find behavioural impairments indicating that attentional abilities and object recognition are not impacted by reduced oligodendrogenesis and hippocampal Dusp15 expression. Gaining insight into the role of newly formed oligodendrocytes and Dusp15 expression is helpful for the development of well targeted treatments for myelin dysregulation.

Definition of the contribution of an Osteopontin-producing CD11c

Alzheimers disease (AD) is the most common form of incurable dementia and represents a critical public health issue as the worlds population ages. Although microglial dysregulation is a cardinal feature of AD, the extensive heterogeneity of these immunological cells in the brain has impeded our understanding of their contribution to this disease. Here, we identify a pathogenic microglial subset which expresses the CD11c surface marker as the sole producer of Osteopontin (OPN) in the 5XFAD mouse model of AD. OPN production divides Disease-Associated Microglia (DAM) into two functionally distinct subsets, i.e., a protective CD11c

Tilavonemab in early Alzheimers disease results from a phase 2, randomized, double-blind study.

Tau accumulation in patients with Alzheimers disease tracks closely with cognitive decline and plays a role in the later stages of disease progression. This phase 2 study evaluated the safety and efficacy of tilavonemab, an anti-tau monoclonal antibody, in patients with early Alzheimers disease. In this 96-week, randomized, double-blind, placebo-controlled study (NCT02880956), patients aged 55-85 years meeting clinical criteria for early Alzheimers disease with a Clinical Dementia Rating-Global Score of 0.5, a Mini Mental State Examination score of 22 to 30, a Repeatable Battery for the Assessment of Neuropsychological Status-Delayed Memory Index score of ≤85, and a positive amyloid PET scan were randomized 1111 to receive one of three doses of tilavonemab (300 mg, 1000 mg, or 2000 mg) or placebo via intravenous infusion every four weeks. The primary endpoint was the change from baseline up to Week 96 in the Clinical Dementia Rating-Sum of Boxes score. Safety evaluations included adverse event monitoring and MRI assessments. A total of 453 patients were randomized, of whom 337 were treated with tilavonemab (300 mg, n 108 1000 mg, n 116 2000 mg, n 113) and 116 received placebo. Baseline demographics and disease characteristics were comparable across groups. The mean age was 71.3 (standard deviation SD 7.0) years, 51.7% were female, and 96.5% were White. At baseline, the mean CDR-SB score was 3.0 (1.2), which worsened through Week 96 for all treatment groups. The least squares mean change from baseline at Week 96 in the CDR-SB score with tilavonemab was not significantly different compared with placebo (300 mg n 85 -0.07 95% confidence interval (CI) -0.83 to 0.69 1000 mg n 91 -0.06 95% CI -0.81 to 0.68 2000 mg n 81 0.16 95% CI -0.60 to 0.93 all P ≥ 0.05). The incidence of any adverse event and MRI findings were generally comparable across groups.Tilavonemab was generally well tolerated but did not demonstrate efficacy in treating patients with early Alzheimers disease. Further investigations of tilavonemab in early Alzheimers disease are not warranted.

A review of the application of three-dimensional convolutional neural networks for the diagnosis of Alzheimers disease using neuroimaging.

Alzheimers disease (AD) is a degenerative disorder that leads to progressive, irreversible cognitive decline. To obtain an accurate and timely diagnosis and detect AD at an early stage, numerous approaches based on convolutional neural networks (CNNs) using neuroimaging data have been proposed. Because 3D CNNs can extract more spatial discrimination information than 2D CNNs, they have emerged as a promising research direction in the diagnosis of AD. The aim of this article is to present the current state of the art in the diagnosis of AD using 3D CNN models and neuroimaging modalities, focusing on the 3D CNN architectures and classification methods used, and to highlight potential future research topics. To give the reader a better overview of the content mentioned in this review, we briefly introduce the commonly used imaging datasets and the fundamentals of CNN architectures. Then we carefully analyzed the existing studies on AD diagnosis, which are divided into two levels according to their inputs 3D subject-level CNNs and 3D patch-level CNNs, highlighting their contributions and significance in the field. In addition, this review discusses the key findings and challenges from the studies and highlights the lessons learned as a roadmap for future research. Finally, we summarize the paper by presenting some major findings, identifying open research challenges, and pointing out future research directions.

Design and validation of the 1-week memory battery for assessing episodic memory and accelerated long-term forgetting in cognitively unimpaired subjects.

Subtle decline in memory is thought to arise in the preclinical phase of Alzheimers disease (AD). However, detecting these initial cognitive difficulties cross-sectionally has been challenging, and the exact nature of the decline is still debated. Accelerated long-term forgetting (ALF) has been recently suggested as one of the earliest and most sensitive indicators of memory dysfunction in subjects at risk of developing AD. The objective of this study was to design and validate the 1-week memory battery (1WMB) for assessing episodic memory and ALF in cognitively unimpaired individuals. The 1WMB is unique in that it assesses multimodal memory and measures recall at both short delay (20 min) and at long term (1 week). Forty-five cognitively unimpaired subjects were assessed with 1WMB and standardized neuropsychological tests. Subjective cognitive decline (SCD), levels of anxiety and depression, and cognitive reserve were also measured. The tests of 1WMB showed a high internal consistency, and concurrent validity was observed with standard tests of episodic memory and executive functions. The analysis revealed a greater loss of information at 1 week compared to short-term forgetting (20 min). Performance in the 1WMB was affected by age and educational level, but was not associated with levels of anxiety and depression. Unlike standard tests, performance in the 1WMB correlated with measures of SCD. Our findings indicate that the 1WMB has good psychometric properties, and future studies are needed to explore its potential usefulness to assess cognitively unimpaired subjects at increased risk of developing AD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genetically downregulated Interleukin-6 signalling is associated with a lower risk of frailty.

numerous studies point towards a critical role of Interleukin 6 (IL-6) pathway in frailty pathogenesis yet the causal relationship between the two remains elusive. we selected genetic variants near the IL-6 receptor locus (IL-6R) associated with reduced C-reactive protein (CRP) levels, a downstream effector of IL-6 pathway, and we used them as genetic proxies of IL-6 signalling downregulation. We then performed a two-sample Mendelian randomisation (MR) to investigate the association with frailty status, as defined by the Frailty Index (FI) in 11,171 individuals from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD) study. MR analysis was repeated after excluding depression or cognition-related FI items as well as following age or sex stratification. Association with frailty was also examined using an alternative instrument, weighted on s-IL-6R levels. Replication was attempted in UK Biobank dataset. genetic predisposition to IL-6 signalling downregulation, weighted on CRP levels, was associated with lower risk of frailty, inserted either as categorical (odds ratio 95% confidence interval 0.15 -3.39, -0.40, P 0.013) or continuous variable (beta se -0.09 0.003, P 0.0009). Sensitivity analyses revealed similar estimates across different MR methods with no evidence for horizontal pleiotropy or heterogeneity. Results remained robust after exclusion of depression or cognition-related FI items and following sex or age stratification. Genetically increased s-IL-6R levels were negatively correlated with frailty and this finding remained significant in a meta-analysis of UK Biobank and HELIAD cohorts. our results support a potential causal effect of IL-6 signalling on frailty and further suggest that downregulation of IL-6 levels may reduce frailty risk.

Immortalized Alzheimers Disease Astrocytes Characterization of Their Proteolytic Systems.

Alzheimers disease (AD) is a progressive neurodegeneration with dysfunctions in both the ubiquitin-proteasome system (UPS) and autophagy. Astroglia participation in AD is an attractive topic of research, but molecular patterns are partially defined and available in vitro models have technical limitations. Immortalized astrocytes from the hippocampus of 3xTg-AD and wild-type mice (3Tg-iAstro and WT-iAstro, respectively) have been obtained as an attempt to overcome primary cell line limitations and this study aims at characterizing their proteolytic systems, focusing on UPS and autophagy. Both 26S and 20S proteasomal activities were downregulated in 3Tg-iAstro, in which a shift in catalytic subunits from constitutive 20S proteasome to immunoproteasome occurred, with consequences on immune functions. In fact, immunoproteasome is the specific complex in charge of clearing damaged proteins under inflammatory conditions. Parallelly, augmented expression and activity of the lysosomal cathepsin B, enhanced levels of lysosomal-associated membrane protein 1, beclin1, and LC3-II, together with an increased uptake of monodansylcadaverine in autophagic vacuoles, suggested autophagy activation in 3Tg-iAstro. The two proteolytic pathways were linked by p62 that accumulated in 3Tg-iAstro due to both increased synthesis and decreased degradation in the UPS defective astrocytes. Treatment with 4-phenylbutyric acid, a neuroprotective small chemical chaperone, partially restored proteasome and autophagy-mediated proteolysis in 3Tg-iAstro. Our data shed light on the impaired proteostasis in 3Tg-iAstro with proteasome inhibition and autophagic compensatory activation, providing additional validation of this AD in vitro model, and propose a new mechanism of action of 4-phenylbutyric acid in neurodegenerative disorders.

National trends in osteoporosis medication use among Medicare beneficiaries with and without Alzheimers diseaserelated dementias.

Osteoporotic fractures are a leading cause of disability and premature death in the elderly. Patients with Alzheimers and related dementia (ADRD) have high rates of osteoporosis (OP) and substantial risk of osteoporotic fractures. Yet research is sparse on trends and predictors of OP medication use in ADRD. Medicare beneficiaries with OP aged ≥ 67 years have Medicare parts ABD without HMO from 2016 to 2018. Our outcome was receipt of OP medications in 2018. A multivariable logistic regression assessed association between ADRD and OP drug prescribing, adjusted for age, sex, race, region, Medicare entitlement, dual Medicaid eligibility, chronic conditions, number of provider visitshospitalizations, and nursing home (NH) resident status. AgeADRD and NH residencyADRD interactions were tested. Our sample consisted of 47,871 people with OP and ADRD and 201,840 with OP without ADRD. OP drug use was 38.6% in ADRD patients vs. 52.7% in non-ADRD. After adjustment for demographics, chronic conditions, and previous hospitalizationsphysician visits, the OR for OP drug in ADRD vs. non-ADRD was 0.85 (95% CI 0.83-0.87). NH residents had lower odds for OP medication (OR 0.61, 95% CI 0.58-0.64). There were significant interactions between ADRD and age, and between ADRD and NH residency. The OR for OP drug use associated with ADRD was 0.88 (95% CI 0.86-0.90) among community-dwelling elders and 0.66 (95% CI 0.64-0.69) among NH residents. ADRD patients received OP drugs at a lower rate than their non-ADRD counterparts. More research is needed on when to prescribe or deprescribe OP drugs in the context of different ADRD severity, patient preferences, remaining life expectancy, and time-to-benefit from OP drugs.

Investigation of biological activities of two cultivars of Cicer arietinum proteins mass associated with Alzheimers disease.

Alzheimers disease (AD) is the most common cause of dementia in the elderly, with some known classical factors. Cicer arietinum (Leguminosae) is a source of protein for humans and contains albumin, globulin, glutelin, and prolamin. The protein content of two cultivars of C. arietinum, Hashem and Mansour, was isolated to evaluate their inhibition activity against acetylcholinesterase (AChE), butyrylcholine esterase (BChE), and β-amyloid peptide (βA) aggregation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and molecular docking were also applied to evaluate the content and determine the potential of each chickpea protein to interact with AChE, respectively. Obtained data showed that proteins from both cultivars could inhibit AChE with IC50 of 17.73 (0.03) and 22.20 (0.06) μgmL, respectively, with no activity on BChE. The 50 μgmL protein concentration of each cultivar suppressed βA accumulation (Mansour 25.66 % and Hashem 21.69 %) and showed bio-metal chelating activity. SDS-PAGE analysis revealed relatively different protein patterns, though the Mansour cultivar contained some protein bands with molecular weights of 18, 24, and 70 KDa were estimated to belong to vicilin and legumin, which were absent in the Hashem protein mass. Molecular docking showed that legumin and especially vicilin have good potential to interact with AChE. The chickpea proteins showed inhibitory activity against AChE, which might be due to the vicilin and legumin fractions. The characterization of the inhibitory effect of each protein band could be promising in finding new therapeutic peptide candidates to treat Alzheimers in the future, although more experimental work is needed in this issue. This article is protected by copyright. All rights reserved.

Selenium-enriched foods and their ingredients As intervention for the vicious cycle between autophagy and overloaded stress responses in Alzheimers disease.

Dysfunctional autophagy induced by excessive reactive oxygen species (ROS) load and inflammation accelerates the development of Alzheimers disease (AD). Recently, there has been an increasing interest in selenium-enriched ingredients (SEIs), such as selenoproteins, selenoamino acids and selenosugars, which could improve AD through antioxidant and anti-inflammation, as well as autophagy modulating effects. This review indicates that SEIs eliminate excessive ROS by activating the nuclear translocation of nuclear factor erythroid2-related factor 2 (Nrf2) and alleviate inflammation by inhibiting the mitogen-activated protein kinases (MAPKs)nuclear factor kappa-B (NF-

Combinations of Vitamin A and Vitamin E Metabolites Confer Resilience against Amyloid-β Aggregation.

Alzheimers disease is characterized by the presence in the brain of amyloid plaques formed by the aberrant deposition of the amyloid-β peptide (Aβ). Since many vitamins are dysregulated in this disease, we explored whether these molecules contribute to the protein homeostasis system by modulating Aβ aggregation. By screening 18 fat-soluble and water-soluble vitamin metabolites, we found that retinoic acid and α-tocopherol, two metabolites of vitamin A and vitamin E, respectively, affect Aβ aggregation both in vitro and in a

Vanillin Benzothiazole Derivative Reduces Cellular Reactive Oxygen Species and Detects Amyloid Fibrillar Aggregates in Alzheimers Disease Brain.

The misfolding of amyloid beta (Aβ) peptides into Aβ fibrillary aggregates is a major hallmark of Alzheimers disease (AD), which responsible for the excess production of hydrogen peroxide (H

Rapamycin and Alzheimer disease a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease.

In 2019 we summarized work relating to the potential use of rapamycin for treating Alzheimer disease (AD). We considered the commentary necessary because use of rapamycin in people with AD is a very real prospect and we wanted to present a balanced view of the likely consequences of MTOR (mechanistic target of rapamycin kinase) inhibition in the AD brain. We concluded that use of rapamycin, an MTOR inhibitor that increases macroautophagyautophagy, could hold promise for prevention of AD if used early enough. However, MTOR inhibition appeared ineffectual in resolving existing amyloid pathology in AD mouse models. In this View article, we update these observations with new studies that have used rapamycin in AD models and provide evidence both for and against its use in AD. We also discuss rapamycin in the light of new research that describes rapamycin-induced autophagic stress in the aging brain and autophagic stress as the origin of the amyloid plaque itself. We conclude that rapamycin will have complex effects on the brain in AD. Further, we hypothesize that lysosomal degradative capacity in the brain will likely determine how effective or detrimental rapamycin will be as a treatment of AD.

A glycine-serine-alanine-rich peptide ameliorates Alzheimer-type neurodegeneration.

Repeated amino acid sequences are widely existing, and the glycine-serine-alanine repeat is an element with the similar general propensity of key pathological factors across neurodegenerative diseases to form β-sheet aggregation. The property of this repeat may shed light on exploration of disease-modifying therapies for neurodegenerative disease, however, its specific role and underlying mechanism remain largely unknown. Using transgenic mice and C. elegans, and rat and cell models of Alzheimers disease (AD), we evaluated the actions of specific glycine-serine-alanine repeat peptide SNP especially SNP-9 on AD-like abnormalities. Entrance of SNP into brain, and SNP activity characteristic in neuronal cell and peptide entrance into cells were analyzed in the in vivo system and in vitro system respectively. The cell-free system and yeast two hybrid system were used to explore the potential target of SNP-9, and the cell-based system was used to confirm the interaction of the intracellular target with SNP-9. Here, we first identify specific glycine-serine-alanine repeat peptide as neuroprotective peptide SNP, and propose SNP especially SNP-9 as potential therapeutic agent for the treatment of AD. SNP-9 can decrease oligomeric Aβ via co-assembling with the toxic Aβ oligomer to form heterooligomers. Furthermore, we identify calcyclin-binding protein as SNP-9 binding protein by screening of a human brain cDNA library, and confirm the vital role of calcyclin-binding protein in regulation of abnormal hyperphosphorylation of tau by SNP-9. Our study provides foundations for development of glycine-serine-alanine repeat peptides especially SNP-9 as potential therapeutic interventions for AD.

One-year prediction of cognitive decline following cognitive-stimulation from real-world data.

Clinical evidence based on real-world data (RWD) is accumulating exponentially providing larger sample sizes available, which demand novel methods to deal with the enhanced heterogeneity of the data. Here, we used RWD to assess the prediction of cognitive decline in a large heterogeneous sample of participants being enrolled with cognitive stimulation, a phenomenon that is of great interest to clinicians but that is riddled with difficulties and limitations. More precisely, from a multitude of neuropsychological Training Materials (TMs), we asked whether was possible to accurately predict an individuals cognitive decline one year after being tested. In particular, we performed longitudinal modelling of the scores obtained from 215 different tests, grouped into 29 cognitive domains, a total of 124,610 instances from 7902 participants (40% male, 46% female, 14% not indicated), each performing an average of 16 tests. Employing a machine learning approach based on ROC analysis and cross-validation techniques to overcome overfitting, we show that different TMs belonging to several cognitive domains can accurately predict cognitive decline, while other domains perform poorly, suggesting that the ability to predict decline one year later is not specific to any particular domain, but is rather widely distributed across domains. Moreover, when addressing the same problem between individuals with a common diagnosed label, we found that some domains had more accurate classification for conditions such as Parkinsons disease and Down syndrome, whereas they are less accurate for Alzheimers disease or multiple sclerosis. Future research should combine similar approaches to ours with standard neuropsychological measurements to enhance interpretability and the possibility of generalizing across different cohorts.

Brain-protective mechanisms of autophagy associated circRNAs Kick starting self-cleaning mode in brain cells

Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimers disease, Parkinsons disease, Huntingtons disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreichs ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.

A novel cascade machine learning pipeline for Alzheimers disease identification and prediction.

Alzheimers disease (AD) is a progressive and irreversible brain degenerative disorder early. Among all diagnostic strategies, hippocampal atrophy is considered a promising diagnostic method. In order to proactively detect patients with early Alzheimers disease, we built an Alzheimers segmentation and classification (AL-SCF) pipeline based on machine learning. In our study, we collected coronal T1 weighted images that include 187 patients with AD and 230 normal controls (NCs). Our pipeline began with the segmentation of the hippocampus by using a modified U2-net. Subsequently, we extracted 851 radiomics features and selected 37 features most relevant to AD by the Hierarchical clustering method and Least Absolute Shrinkage and Selection Operator (LASSO) algorithm. At last, four classifiers were implemented to distinguish AD from NCs, and the performance of the models was evaluated by accuracy, specificity, sensitivity, and area under the curve. Our proposed pipeline showed excellent discriminative performance of classification with AD vs NC in the training set (AUC0.97, 95% CI (0.96-0.98)). The model was also verified in the validation set with Dice0.93 for segmentation and accuracy0.95 for classification. The AL-SCF pipeline can automate the process from segmentation to classification, which may assist doctors with AD diagnosis and develop individualized medical plans for AD in clinical practice.

The Effective Components, Core Targets, and Key Pathways of Ginseng against Alzheimers Disease.

TCMSP database was used to screen the active ingredients of A total of 22 bioactive compounds were identified from

Suvorexant, a Novel Dual Orexin Receptor Antagonist, for the Management of Insomnia.

The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexants role in targeting insomnia with other comorbidities. Insomnia refers to poor quality andor quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexants effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimers disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment. Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia.

Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimers disease and amyotrophic lateral sclerosis.

In neurodegenerative diseases such as Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS), the progressive accumulation of ubiquitin-positive cytoplasmic inclusions leads to proteinopathy and neurodegeneration. Along with the seven types of Lys-linked ubiquitin chains, the linear ubiquitin chain assembly complex (LUBAC)-mediated Met1-linked linear ubiquitin chain, which activates the canonical NF-κB pathway, is also involved in cytoplasmic inclusions of tau in AD and TAR DNA-binding protein 43 in ALS. Post-translational modifications, including heterologous ubiquitination, affect proteasomal and autophagic degradation, inflammatory responses, and neurodegeneration. Single nucleotide polymorphisms (SNPs) in

Growing older with intellectual and developmental disabilities implementing and evaluating a project ECHO for dementia education.

The needs of the rapidly expanding population of adults growing older with intellectual and developmental disabilities (IDD) and their families span both the IDD and the aging service systems. The use of Project ECHO (Extension for Community Healthcare Outcomes) for professional education can bridge gaps and span boundaries between them at the macro, meso, and micro levels. A series of 10 ECHO sessions over 12 months was developed, incorporating key content on IDD and ADADRD for 145 providers in over 20 agencies. Impacts were assessed by a follow-up survey sent to participants after each program. The evaluation included quantitative assessment of ECHO features and a retrospective pre- and posttest of knowledge acquisition a separate item assessed intention to apply information. Qualitative data were collected from open-ended items. The case presentation and discussion were the most effective ECHO components. Knowledge acquisition was significant for all sessions most important uses included providing better care to clientspatients, training staff, and educating family andor caregivers. Participants were aligned with two distinct groups, one with a predominant knowledge focus, the other with an emphasis on networking. Project ECHO can bridge gaps and span boundaries between the IDD and aging care systems at multiple levels, improving interprofessional collaboration and care by addressing both knowledge and networking needs of providers.

Aminoadamantanes from treatment of Parkinsons and Alzheimers disease to symptom amelioration of long COVID-19 syndrome

The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists. The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinsons disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimers disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes. The drugs amantadine and memantine are known as aminoadamantanes. Amantadine improves motor skills in patients with Parkinson’s disease. It also reduces fatigue in individuals suffering from multiple sclerosis. Memantine improves memory dysfunction linked to Alzheimer’s disease. Aminoadamantanes affect communication between nerve cells by supporting neurotransmission of monoamines. Clinical studies have found that these drugs benefit patients with chronic neurodegenerative diseases, who have depression, fatigue, loss of attention or concentration deficits. These brain function problems may also appear to some extent due to COVID-19 infection. We suggest that aminoadamantanes could improve these problems in COVID-19 patients in both the short and long term. Clinical research is needed to confirm this hypothesis.

Atypical presentation of Induced Ache-i Diarrhea in elderly people with cognitive decline an aspect not to be underestimated.

The rivastigmine patch is the only existing transdermal delivery system used for the treatment of Alzheimers disease. Among the most common adverse events derived from its use are gastrointestinal events, particularly diarrhea. We report a clinical case of an 81-year-old patient admitted to our hospital under long-standing treatment with rivastigmine transdermal patch who presented with atypical watery diarrhea. Anamnesis showed that the patient presented with a likely infectious gastroenteric event, the diarrheal symptoms of which persisted upon resolution of the event and resolved only upon temporary discontinuation of acetylcholinesterase inhibitors. Failure to rapidly identify the causes of profuse diarrhea in older adults can have lethal consequences. When these symptoms occur, quickly recognizing the causes and providing proper management can be lifesaving.

Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect.

Extracellular vesicles (EVs) are mediators of cellular communication that can be released by almost all cell types in both physiological and pathological conditions and are present in most biological fluids. Such characteristics make them attractive in the research of biomarkers for age-related pathological conditions. Based on this, the aim of the present study was to examine the changes in EV concentration and size in the context of frailty, a geriatric syndrome associated with a progressive physical and cognitive decline. Specifically, total EVs and neural and microglial-derived EVs (NDVs and MDVs respectively) were investigated in plasma of frail and non-frail controls (CTRL), mild cognitive impairment (MCI) subjects, and in Alzheimers disease (AD) patients. Results provided evidence that AD patients displayed diminished NDV concentration (3.61 × 10

Evidence for lecanemab in early Alzheimers disease.

Effect on Danggui Shaoyao Powder on mitophagy in rat model of Alzheimers disease based on PINK1-Parkin pathway.

This study investigated the mechanism of Danggui Shaoyao Powder(DSP) against mitophagy in rat model of Alzheimers disease(AD) induced by streptozotocin(STZ) based on PTEN induced putative kinase 1(PINK1)-Parkin signaling pathway. The AD rat model was established by injecting STZ into the lateral ventricle, and the rats were divided into normal group, model group, DSP low-dose group(12 g·kg(-1)·d(-1)), DSP medium-dose group(24 g·kg(-1)·d(-1)), and DSP high-dose group(36 g·kg(-1)·d(-1)). Morris water maze test was used to detect the learning and memory function of the rats, and transmission electron microscopy and immunofluorescence were employed to detect mitophagy. The protein expression levels of PINK1, Parkin, LC3BⅠLC3BⅡ, and p62 were assayed by Western blot. Compared with the normal group, the model group showed a significant decrease in the learning and memory function(Plt0.01), reduced protein expression of PINK1 and Parkin(Plt0.05), increased protein expression of LC3BⅠLC3BⅡ and p62(Plt0.05), and decreased occurrence of mitophagy(Plt0.01). Compared with the model group, the DSP medium-and high-dose groups notably improved the learning and memory ability of AD rats, which mainly manifested as shortened escape latency, leng-thened time in target quadrants and elevated number of crossing the platform(Plt0.05 or Plt0.01), remarkably activated mitophagy(Plt0.05), up-regulated the protein expression of PINK1 and Parkin, and down-regulated the protein expression of LC3BⅠLC3BⅡ and p62(Plt0.05 or Plt0.01). These results demonstrated that DSP might promote mitophagy mediated by PINK1-Parkin pathway to remove damaged mitochondria and improve mitochondrial function, thereby exerting a neuroprotective effect.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease using systematic reviews to inform expert consensus.

Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimers disease, Huntingtons disease, Parkinsons disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. From the clinical review, we identified 595 interventions. 66 drugs met our drugdisease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Abnormal posture of the trunk related to donepezil hydrochloride report of 2 cases.

Patient 1, an 80-year-old woman with Alzheimers disease, had been taking donepezil 5 mg for 2 years. Donepezil was increased to 10 mg, and 2 months later, the patient developed dropped head syndrome. MRI and needle EMG abnormality of the neck extensor muscles suggested focal myopathy, but the symptom disappeared within 2 months by discontinuing donepezil. Patient 2, a 78-year-old man with Lewy body dementia, had been taking levodopa and pramipexole (PPX). One month after tapering levodopa, donepezil 3 mg was introduced, and Pisa syndrome (bending of the trunk to the right anterior direction) developed 10 days later. Donepezil and PPX were discontinued and levodopa was increased. Within 5 months, his posture had almost recovered. Cholinesterase inhibitors can induce abnormal posture of the trunk, and clinicians should be aware of this uncommon but important side effect.

Chronic Treatment with Aβ42 with a Toxic Conformer and LPS Induces Inflammatory Responses in BV-2 Microglia with Dysregulation of Hypoxia-Inducible Factor Expression.

Amyloid β (Aβ) plays a key role in the pathology of Alzheimers disease (AD) and is toxic owing to its ability to aggregate into oligomers and fibrils. Aβ has high aggregative ability and potent toxicity due to the toxic turn at positions 22 and 23. Furthermore, APP knock-in mice producing E22P-Aβ with the toxic turn exhibited AD-related phenotypes such as cognitive impairment, Aβ plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of AD-related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by E22P-Aβ with the toxic turn. Here, we investigated the effects of chronic treatment with E22P-Aβ42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with E22P-Aβ42 and LPS increased nitric oxide production and the expression of interleukin-6 (IL-6), whereas it reduced the expression of HIF-1α and HIF-3α in BV-2 microglia. The reduction of HIF-1α caused by E22P-Aβ42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with E22P-Aβ42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-κB). E22P-Aβ42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of AD pathology.

Plantainoside B in Bacopa monniera Binds to Aβ Aggregates Attenuating Neuronal Damage and Memory Deficits Induced by Aβ.

Alzheimers disease (AD) is a progressive neurodegenerative disease characterized by dementia. The most characteristic pathological changes in AD brain include extracellular amyloid-β (Aβ) accumulation and neuronal loss. Particularly, cholinergic neurons in the nucleus basalis of Meynert are some of the first neuronal groups to degenerate accumulating evidence suggests that Aβ oligomers are the primary form of neurotoxicity. Bacopa monniera is a traditional Indian memory enhancer whose extract has shown neuroprotective and Aβ-reducing effects. In this study, we explored the low molecular weight compounds from B. monniera extracts with an affinity to Aβ aggregates, including its oligomers, using Aβ oligomer-conjugated beads and identified plantainoside B. Plantainoside B exhibited evident neuroprotective effects by preventing Aβ attachment on the cell surface of human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. Moreover, it attenuated memory impairment in mice that received intrahippocampal Aβ injections. Furthermore, radioisotope experiments revealed that plantainoside B has affinity to Aβ aggregates including its oligomers and brain tissue from a mouse model of Aβ pathology. In addition, plantainoside B could delay the Aβ aggregation rate. Accordingly, plantainoside B may exert neuroprotective effects by binding to Aβ oligomers, thus interrupting the binding of Aβ oligomers to the cell surface. This suggests its potential application as a theranostics in AD, simultaneously diagnostic and therapeutic drugs.

Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment.

COVID-19 is a complex disease with short-term and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. As many drugs targeting single targets showed only limited effectiveness against COVID-19, here, we aimed to explore a multi-target strategy. We synthesized a focused compound library based on C2-substituted indolealkylamines (tryptamines and 5-hydroxytryptamines) with activity for three potential COVID-19-related proteins, namely melatonin receptors, calmodulin and human angiotensin converting enzyme 2 (hACE2). Two molecules from the library, 5e and h, exhibit affinities in the high nanomolar range for melatonin receptors, inhibit the calmodulin-dependent calmodulin kinase II activity and the interaction of the SARS-CoV-2 Spike protein with hACE2 at micromolar concentrations. Both compounds inhibit SARS-CoV-2 entry into host cells and 5h decreases SARS-CoV-2 replication and M

Protective effects of berberine against β-amyloid-induced neurotoxicity in HT22 cells via the Nrf2HO-1 pathway.

Neuronal apoptosis has been found to have a pivotal role in the course of Alzheimers disease (AD). Berberine (BBR), a potent antioxidant, occurs in plants such as Berberis, Phellodendron chinense, and Hydrastis canadensis. In this study, a neuronal apoptotic model was established in vitro using HT22 cells induced by Aβ

Clinical relevance of disrupted topological organization of anatomical connectivity in behavioral variant frontotemporal dementia.

Graph theory is a novel approach used to examine the balance of brain connectomes. However, the clinical relevance of white matter (WM) connectome changes in the behavioral variant frontotemporal dementia (bvFTD) is not well understood. We aimed to investigate the clinical relevance of WM topological alterations in bvFTD. Thirty patients with probable bvFTD and 30 healthy controls underwent diffusion tensor imaging, structural MRI, and neuropsychological assessment. WM connectivity between 90 brain regions was calculated and the graph approach was applied to capture the individual characteristics of the anatomical network. Voxel-based morphometry and tract-based spatial statistics were used to present the gray matter atrophy and disrupted WM integrity. The topological organization was disrupted in patients with bvFTD both globally and locally. Compared to controls, bvFTD data showed a different pattern of hub region distributions. Notably, the nodal efficiency of the right superior orbital frontal gyrus was associated with apathy and disinhibition. Topological measures may be potential image markers for early diagnosis and disease severity monitoring of bvFTD.

Zinc-Epigallocatechin-3-gallate Network-Coated Nanocomposites against the Pathogenesis of Amyloid-Beta.

The aggregation of amyloid beta (Aβ) is a hallmark of Alzheimers disease (AD), a major cause of dementia and an unmet challenge in modern medicine. In this study, we constructed a biocompatible metal-phenolic network (MPN) comprising a polyphenol epigallocatechin gallate (EGCG) scaffold coordinated by physiological Zn(II). Upon adsorption onto gold nanoparticles, the MPNAuNP nanoconstruct elicited a remarkable potency against the amyloid aggregation and toxicity of Aβ in vitro. The superior performance of MPNAuNP over EGCGAuNP was attributed to the porosity and hence larger surface area of the MPN in comparison with that of EGCG alone. The atomic detail of Zn(II)-EGCG coordination was unraveled by density functional theory calculations and the structure and dynamics of Aβ aggregation modulated by the MPN were further examined by discrete molecular dynamics simulations. As MPNAuNP also displayed a robust capacity to cross a blood-brain barrier model through the paracellular pathway, and given the EGCGs function as an anti-amyloidosis and antioxidation agent, this MPN-based strategy may find application in regulating the broad AD pathology beyond protein aggregation inhibition.

Comprehensive Review on Potential Signaling Pathways Involving the Transfer of α-Synuclein from the Gut to the Brain That Leads to Parkinsons Disease.

Parkinsons disease is the second most prevalent neurological disease after Alzheimers. Primarily, old age males are more affected than females. The aggregates of oligomeric forms of α-synuclein cause the loss of dopaminergic neurons in the substantia nigra pars compacta. Further, it leads to dopamine shortage in the striatum region. According to recent preclinical studies, environmental factors like pesticides, food supplements, pathogens, etc. enter the body through the mouth or nose and ultimately reach the gut. Further, these factors get accumulated in enteric nervous system which leads to misfolding of α-synuclein gene, and aggregation of this gene results in Lewy pathology in the gut and reaches to the brain through the vagus nerve. This evidence showed a strong bidirectional connection between the gut and the brain, which leads to gastrointestinal problems in Parkinson patients. Moreover, several studies reveal that patients with Parkinson experience more gastrointestinal issues in the early stages of the disease, such as constipation, increased motility, gut inflammation, etc. This review article focuses on the transmission of α-synuclein and the mechanisms involved in the link between the gut and the brain in Parkinsons disease. Also, this review explores the various pathways involved in Parkinson and current therapeutic approaches for the improvement of Parkinsons disease.

Evaluating interpersonal discrimination and depressive symptoms as partial mediators of the effects of education on cognition Evidence from the Study of Healthy Aging in African Americans (STAR).

Education is correlated with positive health outcomes, but associations are sometimes weaker among African Americans. The extent to which exposure to discrimination and depressive symptoms attenuates the education-cognition link has not been investigated. Study of Healthy Aging in African Americans (STAR) participants (n 764 average age 69 years) completed the Spanish and English Neuropsychological Assessment Scales. We assessed everyday and major lifetime discrimination and depressive symptoms as mediators of education effects on cognition using G-estimation with measurement error corrections. Education was correlated with greater major lifetime and everyday discrimination but lower depressive symptoms. Accounting for discrimination and depressive symptoms slightly reduced the estimated effect of education on cognition. The estimated total effect of graduate education (vs <Bachelors) was 0.66 (95% confidence interval CI 0.62, 0.68), and the direct effect not mediated by discrimination or depressive symptoms was 0.60 (95% CI 0.43, 0.76). Education has robust effects on later-life cognition after controlling multiple mediating pathways and offsetting mechanisms.

Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.

Alzheimers disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance-based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network-based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.

SynthSR A public AI tool to turn heterogeneous clinical brain scans into high-resolution T1-weighted images for 3D morphometry.

Every year, millions of brain magnetic resonance imaging (MRI) scans are acquired in hospitals across the world. These have the potential to revolutionize our understanding of many neurological diseases, but their morphometric analysis has not yet been possible due to their anisotropic resolution. We present an artificial intelligence technique, SynthSR, that takes clinical brain MRI scans with any MR contrast (T1, T2, etc.), orientation (axialcoronalsagittal), and resolution and turns them into high-resolution T1 scans that are usable by virtually all existing human neuroimaging tools. We present results on segmentation, registration, and atlasing of >10,000 scans of controls and patients with brain tumors, strokes, and Alzheimers disease. SynthSR yields morphometric results that are very highly correlated with what one would have obtained with high-resolution T1 scans. SynthSR allows sample sizes that have the potential to overcome the power limitations of prospective research studies and shed new light on the healthy and diseased human brain.

Social isolation is linked to classical risk factors of Alzheimers disease-related dementias.

Alzheimers disease and related dementias is a major public health burden-compounding over upcoming years due to longevity. Recently, clinical evidence hinted at the experience of social isolation in expediting dementia onset. In 502,506 UK Biobank participants and 30,097 participants from the Canadian Longitudinal Study of Aging, we revisited traditional risk factors for developing dementia in the context of loneliness and lacking social support. Across these measures of subjective and objective social deprivation, we have identified strong links between individuals social capital and various indicators of Alzheimers disease and related dementias risk, which replicated across both population cohorts. The quality and quantity of daily social encounters had deep connections with key aetiopathological factors, which represent 1) personal habits and lifestyle factors, 2) physical health, 3) mental health, and 4) societal and external factors. Our population-scale assessment suggest that social lifestyle determinants are linked to most neurodegeneration risk factors, highlighting them as promising targets for preventive clinical action.

Dynamic network modeling of gut microbiota during Alzheimers disease progression in mice.

The intimate association between the gut microbiota (GM) and the central nervous system points to potential intervention strategies for neurological diseases. Nevertheless, there is currently no theoretical framework for selecting the window period and target bacteria for GM interventions owing to the complexity of the gut microecosystem. In this study, we constructed a complex network-based modeling approach to evaluate the topological features of the GM and infer the window period and bacterial candidates for GM interventions. We used Alzheimers disease (AD) as an example and traced the GM dynamic changes in AD and wild-type mice at one, two, three, six, and nine months of age. The results revealed alterations of the topological features of the GM from a scale-free network into a random network during AD progression, indicating severe GM disequilibrium at the late stage of AD. Through stability and vulnerability assessments of the GM networks, we identified the third month after birth as the optimal window period for GM interventions in AD mice. Further computational simulations and robustness evaluations determined that the hub bacteria were potential candidates for GM interventions. Moreover, our GM functional analysis suggested that

Metformin mitigates amyloid β

Metformin is an antidiabetic medicine widely used for management of type 2 diabetes with neuroprotective effects and promising potential to attenuate cognitive impairment. The efficacy of metformin in attenuation of Alzheimers disease (AD) pathology has not been well-documented. Thus, this study was designed to assess protective effect of metformin against Aβ

Research progress of PPARγ regulation of cholesterol and inflammation in Alzheimers disease.

Peroxidase proliferator receptors (PPARs) are defined as key sensors and regulators of cell metabolism, transcription factors activated by ligands, involved in lipid, glucose and amino acid metabolism, participating in the processes of cell differentiation, apoptosis, inflammation regulation, and acute and chronic nerve damage. Among them, PPARγ is expressed in different brain regions and can regulate lipid metabolism, mitochondrial disorders, oxidative stress, and cell apoptosis. It has anti-inflammatory activity and shows neuroprotection. The regulation of Aβ levels in Alzheimers disease involves cholesterol metabolism and inflammation, so this article first analyzes the biological functions of PPARγ, then mainly focuses on the relationship between cholesterol and inflammation and Aβ, and elaborates on the regulation of PPARγ on key proteins and the corresponding molecules, which provides new ideas for the treatment of AD.

Drawing a line-Visuo-constructive function as discriminator between healthy individuals, subjective cognitive decline, mild cognitive impairment and Alzheimers disease and predictor of disease progress compared to a multimodal approach.

One cognitive domain impaired in Alzheimers disease (AD) is visuo-construction. The Vienna Visuo-constructional Test 3.0 Screening (VVT 3.0 Screening) measures this cognitive domain. This study examines how it works in the differentiation of AD from healthy controls (HC) and the prodromal stages subjective cognitive decline (SCD) and mild cognitive impairment (MCI) and also how it performs in prediction of progress compared to the Mini Mental State Examination (MMSE) and the Sunderland Clock Drawing Test (CDT). Data from 622 patients (33 HC, 68 SCD, 301 MCI, 220 AD) who completed all three tests were obtained. Furthermore, 117 patients were examined in a follow-up. Data were analyzed in a retrospective analysis comparing the validity of tests in diagnosis and prediction using receiver operator characteristic (ROC) curves and multinominal logistic regression. The VVT 3.0 Screening shows some ability to discriminate between AD and all other participants (sensitivity 62.1%, specificity 83.1%), while of the three examined tests none was able to predict membership to all experimental groups or to predict disease-progress adequately. As the VVT 3.0 Screening is short, easy to apply and largely language independent, it can be considered an alternative to the MMSE in certain situations. The VVT 3.0 Screening is useful to discriminate between AD and all other participants and can be an alternative to the MMSE in certain situations. ZIEL Eine kognitive Domäne, die zur Diagnostik der Alzheimer-Erkrankung genutzt werden kann, ist die Visuokonstruktion. Die Messung kann mittels Vienna Visuo-constructional Test 3.0 Screening (VVT 3.0 Screening) erfolgen. In der vorliegenden Studie wird untersucht, ob der Test die Alzheimer-Erkrankung (AD) von ihren Prodromalstadien subjektiver kognitiver Abbau (SCD), leichte kognitive Beeinträchtigung (MCI) und gesunden Kontrollen (HC) besser unterscheiden kann als der Uhrentest nach Sunderland (CDT) und der Mini-Mental-Status-Test (MMSE). Die drei Tests werden außerdem hinsichtlich ihrer Nützlichkeit zur Vorhersage der Krankheitsprogression verglichen. Insgesamt 622 ProbandInnen (33 HC, 68 SCD, 301 MCI, 220 AD) absolvierten alle drei Tests. Davon nahmen 117 an einer Folgeuntersuchung teil. In einer retrospektiven Datenanalyse wurden Receiver-operating-characteristics(ROC)-Kurven sowie eine multinomiale logistische Regression eingesetzt, um die Validität der drei Tests in Diagnostik und Vorhersage zu bestimmen. Der VVT 3.0 Screening kann zwischen AD und Nicht-AD unterscheiden (Sensitivität 62,1 %, Spezifität 83,1 %). Keiner der drei Tests unterschied jedoch zuverlässig alle Experimentalgruppen oder sagte den Krankheitsverlauf adäquat vorher. Der VVT 3.0 Screening als kürzerer und weniger von Sprachverständnis abhängige Test zeigt ausreichend Validität hinsichtlich der Fragestellung, um als Alternative zu gelten. Der VVT 3.0 Screening ist nützlich, um Nicht-Alzheimer-PatientInnen von Alzheimer-PatientInnen zu unterscheiden und stellt in bestimmten Fällen eine Alternative zum MMSE dar.

Policosanol protects against Alzheimers disease-associated spatial cognitive decline in male rats possible involved mechanisms.

Alzheimers disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and synaptic failure. The present study was designed to explore the possible protective effects of policosanol (PCO) on spatial cognitive capacity, long-term potentiation (LTP) induction, oxidantantioxidant status, and Aβ plaques formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ Healthy adult male Wistar rats were randomly divided into control, sham (ICV injection of 5 µl phosphate-buffered saline), AG (50 mgkg P.O., as PCO vehicle), PCO (50 mgkg P.O.), AD model (ICV injection of 5 µl Aβ), AD AG (50 mgkg P.O.), and AD PCO (50 mgkg P.O.). Treatments were performed for eight consecutive weeks. At the end of the treatment course, spatial learning and memory functions, hippocampal long-term potentiation (LTP) induction, malondialdehyde (MDA), and total thiol group (TTG) levels, as well as the formation of Aβ plaques, were examined. The results showed that injection of Aβ reduced spatial learning and memory abilities in the Barnes maze test, which was accompanied by decreases in field excitatory postsynaptic potential (fEPSP) slope, population spike (PS) amplitude, and TTG level and increases in Aβ plaque accumulation and MDA content. In contrast, PCO treatment improved all the above-mentioned changes in the Aβ-infused rats. The results suggest that amelioration of hippocampal synaptic plasticity impairment, modulation of oxidantantioxidant status, and inhibition of Aβ plaque formation by PCO may be the mechanisms behind its protective effect against AD-associated spatial cognitive decline.

Cognitive trajectories diverge by genetic risk in a preclinical longitudinal cohort.

We sought to characterize the timing of changes in cognitive trajectories related to genetic risk using the apolipoprotein E (APOE) score, a continuous measure of Alzheimers disease (AD) risk. We also aimed to determine whether that timing was different when genetic risk was measured using an AD polygenic risk score (PRS) that contains APOE. We analyzed trajectories (N ≈1135) for four neuropsychological composite scores using mixed effects regression for longitudinal change across APOE scores and PRS of participants in the Wisconsin Registry for Alzheimers Prevention, a longitudinal study of adults aged 40 to 70 at baseline, with a median participant follow-up time of 7.8 years. We found a significant non-linear age-by-APOE score interaction in predicting cognitive decline. Cognitive trajectories diverged by APOE score at approximately 65 years of age. A 0.5 standard deviation difference in cognition between extreme percentiles of the PRS was predicted to occur 1 to 2 years before that of the APOE score. Cognitive decline differs across time and APOE score. Estimates did not substantially shift with the AD PRS. The apolipoprotein E (APOE) score, a continuous measure, accounts for non-linear genetic risk of Alzheimers disease. Non-linear age interacts with the APOE score to affect cognition. Cognitive decline starts to differ by APOE score levels at approximately age 65. Cognitive decline timing by polygenic risk (including APOE) is similar to APOE alone.

Heteromultivalent scaffolds fabricated by biomimetic co-assembly of DNA-RNA building blocks for the multi-analysis of miRNAs.

Heteromultivalent scaffolds with different repeated monomers have great potential in biomedicine, but convenient construction strategies for integrating various functional modules to achieve multiple biological functions are still lacking. Here, taking advantage of the heteromultivalent effect of dendritic nucleic acids and the specific biochemical properties of microRNAs (miRNAs), we assembled novel heteromultivalent nucleic acid scaffolds by biomimetic co-assembly of DNA-RNA building blocks. In our approach, two miRNAs were used to initiate and maintain dendritic structures in an interdependent manner so, the heteromultivalent nanostructure can only form in the presence of both miRNAs. The proposed nanostructure can be used for one-step analysis of two miRNAs in an AND logic format. Taking miR-18b-5p and miR-342-3p which are associated with Alzheimers disease as an example, a FRET sensing system was fabricated for the simultaneous analysis of two miRNAs within one hour at picomolar concentration. Further studies show that the designed device may have the potential to distinguish between AD patients and the healthy population by analysis of two miRNAs in CSF (cerebrospinal fluid) samples, suggesting its possible applicability in clinics.

Pre-targeting amyloid-β with antibodies for potential molecular imaging of Alzheimers disease.

With the aim of developing the concept of pretargeted click chemistry for the diagnosis of Alzheimers disease two antibodies specific for amyloid-β were modified to incorporate

Solvent-dependent formation kinetics of L,L-diphenylalanine micronanotubes.

Investigating the molecular mechanism underlying the aggregation process of amyloid fibers is of great importance both for its implications in several degenerative diseases and for the design of new materials based on self-assembly. In particular, micronanotubes of L,L-diphenylalanine have been investigated as a model of amyloid plaques in Alzheimers disease and also for their broad range of physical properties,

A Flower-like Brain Targeted Selenium Nanocluster Lowers the Chlorogenic Acid Dose for Ameliorating Cognitive Impairment in APPPS1 Mice.

Aβ aggregation-related neuroinflammation and imbalance of brain glucose homeostasis play important roles in the pathological process of Alzheimers disease (AD). Chlorogenic acid (CGA) is one of the most common dietary polyphenols with neuroprotective effects. However, due to the low bioavailability of CGA, its application dose is usually high in vivo. In our previous study, the spherical selenium nanoparticles act as drug carriers to improve the bioactivity of resveratrol. Here, the brain-targeting peptide (TGN peptide) and CGA were used to prepare a new flowerlike selenium nanocluster (TGN-CGASeNCs) for enhancing the bioavailability of CGA. After decoration on selenium nanoclusters, the solubility and stability of CGA was obviously increased. Oral administration of a low dose of CGA (80 mgkgbody weight) only slightly inhibited Aβ aggregate-related neuroinflammation and glucose homeostasis disorder in the brain. Moreover, CGA showed less effect on increasing the diversity and richness of gut microbiota. At the same concentration, the CGA-modified selenium nanocluster (CGASeNCs) and TGN-CGASeNCs showed better function in ameliorating the gut microbiota disorder. Especially, TGN-CGASeNCs significantly increased the relative abundance of

Carotid intima media thickness and white matter hyperintensity volume among midlife women.

Carotid atherosclerosis may be associated with brain white matter hyperintensities (WMH). Few studies consider women at midlife, a critical time for womens cardiovascular and brain health. We tested the hypothesis that higher carotid intima media thickness (IMT) would be associated with greater WMH volume (WMHV) among midlife women. We explored interactions by apolipoprotein E (APOE) ε4 status. Two hundred thirty-nine women aged 45 to 67 underwent carotid artery ultrasound, phlebotomy, and magnetic resonance imaging (MRI). One hundred seventy participants had undergone an ultrasound 5 years earlier. Higher IMT was associated with greater whole brain (Bstandard error (SE) 0.77 .31, P 0.01 multivariable) and periventricular (BSE 0.80 .30, P 0.008 multivariable) WMHV. Associations were observed for IMT assessed contemporaneously with the MRI and 5 years prior to the MRI. Associations were strongest for APOE ε4-positive women. Among midlife women, higher IMT was associated with greater WMHV. Vascular risk is critical to midlife brain health, particularly for APOE ε4-positive women.

Vigorous, regular physical exercise may slow disease progression in Alzheimers disease.

Mild to moderate exercise may decrease Alzheimers disease (AD) risk, but the effects of vigorous, regular physical exercise remain unclear. Two patients with initial diagnoses of amnestic mild cognitive impairment (MCI) demonstrated positive AD biomarkers throughout 16 and 8 years of follow-up, with final diagnoses of mild AD and amnestic MCI, respectively. Patient 1 was diagnosed with amnestic MCI at age 64. Neuropsychological testing, magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid imaging PET, and cerebrospinal fluid (CSF) biomarkers during follow-ups remained consistent with AD. By age 80, progression was minimal with Montreal Cognitive Assessment (MoCA) 26 of 30. Patient 2 was diagnosed with amnestic MCI at age 72. Neuropsychological testing, MRI, FDG-PET, and amyloid imaging PET during follow-ups remained consistent with AD. At age 80, MoCA was 27 of 30 with no clinical progression. Both patients regularly performed vigorous, regular exercise that increased after retirementwork reduction. Vigorous, regular exercise may slow disease progression in biomarker-positive amnestic MCI and mild AD.

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD.

We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimers disease (AD). A total of 998 EOAD and 2562 LOAD participants from the National Alzheimers Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately. APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P < 0.0001). The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.

Effect of L-Carnosine in Patients with Age-Related Diseases A Systematic Review and Meta-Analysis.

L-carnosine has been found to have multimodal activity. The aim of this review was to find out the efficacy of L-carnosine in patients with age-related diseases. Clinical studies evaluated the effect of L-carnosine on cancer, cardiovascular disease, diabetes, and neurodegenerative disorders were searched in electronic bibliographic databases. The protocol has been registered with PROSPERO (CRD42022314033). The revised Cochrane risk of bias tool for randomized trials was used to assess all of the reports for risk of bias. RevMan 5.4 was used to conduct the meta-analysis. Following the screening process, 14 papers were selected for systematic review, with 9 of them being qualified for meta-analysis. Many of the included studies showed that L-carnosine has potential therapeutic activity in age related diseases. Results from the meta-analysis showed that in diabetes mellitus, HbA1c mean difference (MD) 95% CI -1.25 (-2.49, -0.022) Clinical studies were conducted to manage chemotherapy induced toxicities and there are no clinical studies available for its anti-cancer use, and the current evidence does not support its use in the treatment of cardiovascular disease.

A Review of the Pathogenesis and Chinese Medicine Intervention of Alzheimers Disease.

Alzheimers disease (AD) is an age-related neurodegenerative disease that is primary characterized as a cognitive disorder. Its pathology is characterized by the formation of senile plaques in the brain from amyloid-beta (Aβ) aggregation, neuronal fibrillary tangles from hyperphosphorylated tau protein aggregation, prolonged inflammatory responses, and neuronal death. The pathogenesis and clinical manifestations of AD are complex, but aging is generally accepted as one of the most important contributing factors. In addition, there are several hypotheses, including the Aβ hypothesis based on amyloid plaques, the tau hypothesis based on neuronal fiber entanglement, the inflammation hypothesis based on long-term inflammatory responses causing brain damage, and the neuroprotection hypothesis based on synaptic dysfunction and neuronal death. Although the pathogenesis of AD has been broadly classified into four major hypotheses, there are multiple forms of interactions, which is one of the reasons for its complex pathogenesis. Numerous epidemiological studies have shown the important role of genes in AD, followed by brain damage, hyperlipidemia, diabetes, hypertension, and obesity as risk factors for the disease. Despite years of research, several mysteries in AD remain unsolved. Drugs based on various pathogenetic hypotheses are being investigated in large numbers, but the effects are unsatisfactory. In recent years, traditional Chinese medicine (TCM) has made excellent progress and is expected to provide a new possibility for AD treatment. In this review, we focus on the latest developments in studies on the risk factors-Aβ aggregates and related factors such as apolipoprotein E, synaptic loss, and fatty acids, and then present the progress in the research of TCM based on the above pathogenesis, intended to provide a research reference and treatment for AD.

The regulatory role of non-coding RNAs and their interactions with phytochemicals in neurodegenerative diseases a systematic review.

Neurodegenerative diseases (NDDs) are on the rise in the world. Therefore, it is a critical issue to reveal the precise pathophysiological mechanisms and novel therapeutic strategies to deal with such conditions. Passing through different mechanisms, non-coding RNAs (ncRNAs) play a pivotal role in NDDs through various mechanisms, by changing the expression of some genes, interference with protein translation and alterations in some signaling pathways. It urges the need to introduce novel strategies and therapeutic agents with multi-targeting potentials. Phytochemicals are hopeful antioxidants and anti-inflammatory agents with promising modulatory roles on dysregulated signaling pathways and protein translation during NDDs. In this study, the role of ncRNAs (e.g. lncRNAs, miRNA, siRNAs and piRNAs) was highlighted in NDDs. This study also aimed to investigate the role of phytochemicals (phenolic compounds, alkaloids, terpenoids and sulfur compounds) in the modulation of ncRNAs during NDDs such as Alzheimers disease, Parkinsons disease, epilepsy, depression and amyotrophic lateral sclerosis.

Deciphering the clinico-radiological heterogeneity of dysexecutive Alzheimers disease.

Dysexecutive Alzheimers disease (dAD) manifests as a progressive dysexecutive syndrome without prominent behavioral features, and previous studies suggest clinico-radiological heterogeneity within this syndrome. We uncovered this heterogeneity using unsupervised machine learning in 52 dAD patients with multimodal imaging and cognitive data. A spectral decomposition of covariance between FDG-PET images yielded six latent factors (eigenbrains) accounting for 48% of variance in patterns of hypometabolism. These eigenbrains differentially related to age at onset, clinical severity, and cognitive performance. A hierarchical clustering on the eigenvalues of these eigenbrains yielded four dAD subtypes, i.e. left-dominant, right-dominant, bi-parietal-dominant, and heteromodal-diffuse. Patterns of FDG-PET hypometabolism overlapped with those of tau-PET distribution and MRI neurodegeneration for each subtype, whereas patterns of amyloid deposition were similar across subtypes. Subtypes differed in age at onset and clinical severity where the heteromodal-diffuse exhibited a worse clinical picture, and the bi-parietal had a milder clinical presentation. We propose a conceptual framework of executive components based on the clinico-radiological associations observed in dAD. We demonstrate that patients with dAD, despite sharing core clinical features, are diagnosed with variability in their clinical and neuroimaging profiles. Our findings support the use of data-driven approaches to delineate brain-behavior relationships relevant to clinical practice and disease physiology.

Oral infection has been implicated in the possible etiology of Alzheimers disease. To detect amyloid-β (Aβ) within microbial biofilms. Freshly extracted teeth ( SEM demonstrated calculus and gutta percha This study detected both soluble and insoluble Aβ fibrils within the EPS of periodontal and endodontic natural biofilm, strongly suggesting its role as an antimicrobial peptide in combatting local infection, with potential risk for cross-seeding into the brain for AD development.

Application of Structural Retinal Biomarkers to Detect Cognitive Impairment in a Primary Care Setting.

Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimers disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD. This study examines the predictive ability of structural retinal biomarkers in detecting cognitive impairment in a primary care setting. Participants were recruited from Alzheimers Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging, and fundus imaging was performed. Data were examined on The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD.

I Will Be Healthy Ideal Self in Patients with Alzheimers Disease.

Within the concept of the self, a distinction can be made between ideal self (i.e., what would like to become) and feared self (i.e., what would not like to become in the future). We investigated ideal self and feared self in patients with mild Alzheimers disease (AD). We have also measured these self-related processes in relation to depression and anxiety. We invited 31 patients with mild AD and 35 control participants to decide whether they would consider the statement (e.g., I will be healthy) as a representation that they would like to acquire (i.e., ideal self) or to avoid (i.e., feared self). Analysis demonstrated that more participants assigned the I will be healthy statement to ideal self than to feared self, and this tendency was observed in both AD participants and controls. Less depression and anxiety were observed in participants who have assigned the I will be healthy statement to their ideal self compared to those who assigned this statement to their feared self, and this was observed in both AD participant and control groups. Our study demonstrates that AD patients tend to endorse positive health traits and to integrate these traits into their ideal self. AD patients tend to endorse health-related images that are associated with hopes when projecting into their future self. This positive projection into the self may create a motivational force (e.g., aspirations and hopes) to embody the healthy self that AD patients desire to be.

A randomized implementation trial to increase adoption of evidence-informed consent practices.

Several evidence-informed consent practices (ECPs) have been shown to improve informed consent in clinical trials but are not routinely used. These include optimizing consent formatting, using plain language, using validated instruments to assess understanding, and involving legally authorized representatives when appropriate. We hypothesized that participants receiving an implementation science toolkit and a social media push would have increased adoption of ECPs and other outcomes. We conducted a 1-year trial with clinical research professionals in the USA ( Participants who engaged more with the toolkit were more likely to have tried to implement an ECP during the trial than participants less engaged with the toolkit or the active control group. However, there were no significant differences in the adoption of ECPs, intention to adopt, or positive attitudes. Participants reported the toolkit and social media push were satisfactory, and participating increased their awareness of ECPs. However, they reported lacking the time needed to engage with the toolkit more fully. Using an implementation science approach to increase the use of ECPs was only modestly successful. Data suggest that having institutional review boards recommend or require ECPs may be an effective way to increase their use.