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Semantic segmentation of human cell nucleus using deep U-Net and other versions of U-Net models.

The deep learning models play an essential role in many areas, including medical image analysis. These models extract important features without human intervention. In this paper, we propose a deep convolution neural network, named as deep U-Net model, for the segmentation of the cell nucleus, a critical functional unit that determines the function and structure of the body. The nucleus contains all kinds of DNA, RNA, chromosomes, and genes governing all life activities, and its disorder may lead to different types of diseases such as cancer, heart disease, diabetes, Alzheimers, etc. If the nucleus structure is known correctly, diseases due to nucleus disorder may be detected early. It may also reduce the drug discovery time if the shape and size of the nucleus are known. We evaluate the performance of the proposed models on the nucleus segmentation data set used by the Data Science Bowl 2018 competition hosted by Kaggle. We compare its performance with that of the U-Net, Attention U-Net, R2U-Net, Attention R2U-Net, and both versions of the U-Net with and without supervision, in terms of loss, dice coefficient, dice loss, intersection over union, and accuracy. Our model performs better than the existing models.

A case of Lewy body disease and anaplastic astrocytoma presenting with atypical parkinsonism.

We report on a patient with atypical parkinsonism due to coexistent Lewy body disease (LBD) and diffuse anaplastic astrocytoma. The patient presented with a mixed cerebellar and parkinsonian syndrome, incomplete levodopa response, and autonomic failure. The clinical diagnosis was multiple system atrophy (MSA). Supportive features of MSA according to the consensus diagnostic criteria included postural instability and early falls, early dysphagia, pyramidal signs, and orofacial dystonia. Multiple exclusion criteria for a diagnosis of idiopathic Parkinsons disease (iPD) were present. Neuropathological examination of the left hemisphere and the whole midbrain and brainstem revealed LBD, neocortical-type consistent with iPD, hippocampal sclerosis, and widespread neoplastic infiltration by an anaplastic astrocytoma without evidence of a space occupying lesion. There were no pathological features of MSA. The classification of atypical parkinsonism was difficult in this patient. The clinical features and disease course were confounded by the coexistent tumor, leading to atypical presentation and a diagnosis of MSA. We suggest that the initial features were due to Lewy body pathology, while progression and ataxia, pyramidal signs, and falls were accelerated by the occurrence of the astrocytoma. Our case reflects the challenges of an accurate diagnosis of atypical parkinsonism, the potential for confounding co-pathology and the need for autopsy examination to reach a definitive diagnosis.

Prevalence and Predictors of Potentially Inappropriate Medications Among Patients Aged ≥65 Years on Hospital Admissions in Kuwait.

Potentially inappropriate medications are major health concerns for patients aged ≥65 years. To investigate the prevalence of potentially inappropriate medications, Beers criteria can be used. We estimated the prevalence of potentially inappropriate medications prescription among patients aged ≥65 years admitted to Kuwaits largest hospital and identified the predictors of prescribing a potentially inappropriate medication. A cross-sectional study was conducted retrospectively using inpatient records from the medical department at the Hospital in Kuwait from 1 January 2019 to 31 December 2019. The latest version of Beers criteria was used to identify potentially inappropriate medications in patients medical records. Data were analyzed descriptively to estimate the prevalence of potentially inappropriate medications and to describe participant characteristics. The predictors of potentially inappropriate medications prescribing were determined using binary logistic regression. A total of 423 medical records of patients were collected. The mean age of the patients admitted was 76 ± 7 years, and 222 of them (52.5%) were women. Upon hospital admission, potentially inappropriate medication was prevalent in 58.4% of patients. The most prevalent potentially inappropriate medications identified were proton pump inhibitors (27.3%), diuretics (21.5%), antipsychotic agents (9%), selective serotonin reuptake inhibitors (5%), and methyldopa (4%). Polypharmacy, Alzheimers disease, depression, irritable bowel syndrome, hypothyroidism, chronic kidney disease were predictors of potentially inappropriate medications prescription. A high prevalence of potentially inappropriate medication prescription was observed among patients aged ≥65 years admitted to a hospital in Kuwait. The most likely predictor of potentially inappropriate medication prescription was polypharmacy.

Diagnosis of coexistent neurodegenerative dementias in multiple sclerosis.

Among people with multiple sclerosis, cognitive impairment occurs commonly and is a potent predictor of disability. Some multiple sclerosis patients present with severe cognitive impairment, and distinguishing multiple sclerosis-related cognitive impairment from co-existent progressive neurodegenerative diseases such as Alzheimer disease poses a diagnostic challenge. The use of biomarkers such as PET and CSF proteins may facilitate this distinction. The study was a retrospective, descriptive study on convenience samples of separate cohorts, one of cognitively impaired multiple sclerosis patients evaluated on autopsy to demonstrate coincidence of both multiple sclerosis and neurodegenerative cognitive diseases. The second cohort were cognitively impaired multiple sclerosis patients evaluated by biomarker to investigate possible additional neurodegenerative cognitive disorders contributing to the cognitive impairment. We investigated selected biomarkers among 31 severely impaired patients (biomarker cohort) and 12 severely impaired patients assessed at autopsy and selected 24 (23 biomarker cohort, 1 autopsy cohort) had comprehensive neurocognitive testing. Biomarker cohort investigations included 18F-Fluorodeoxyglucose PET andor CSF amyloid Aβ1-42, phospho-tau and total tau levels. The autopsy cohort was evaluated with comprehensive neuropathological assessment for aetiology of cognitive impairment. The cohorts shared similar sex, age at multiple sclerosis onset and multiple sclerosis clinical course. The autopsy-cohort patients were older at diagnosis (69.5 versus 57 years,

Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein

Alzheimers disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the

Defining the Dynamic Regulation of O-GlcNAc Proteome in the Mouse Cortex---the O-GlcNAcylation of Synaptic and Trafficking Proteins Related to Neurodegenerative Diseases.

O-linked conjugation of ß-N-acetyl-glucosamine (O-GlcNAc) to serine and threonine residues is a post-translational modification process that senses nutrient availability and cellular stress and regulates diverse biological processes that are involved in neurodegenerative diseases and provide potential targets for therapeutics development. However, very little is known of the networks involved in the brain that are responsive to changes in the O-GlcNAc proteome. Pharmacological increase of protein O-GlcNAcylation by Thiamet G (TG) has been shown to decrease tau phosphorylation and neurotoxicity, and proposed as a therapy in Alzheimers disease (AD). However, acute TG exposure impairs learning and memory, and protein O-GlcNAcylation is increased in the aging rat brain and in Parkinsons disease (PD) brains. To define the cortical O-GlcNAc proteome that responds to TG, we injected young adult mice with either saline or TG and performed mass spectrometry analysis for detection of O-GlcNAcylated peptides. This approach identified 506 unique peptides corresponding to 278 proteins that are O-GlcNAcylated. Of the 506 unique peptides, 85 peptides are elevated by > 1.5 fold in O-GlcNAcylation levels in response to TG. Using pathway analyses, we found TG-dependent enrichment of O-GlcNAcylated synaptic proteins, trafficking, NotchWnt signaling, HDAC signaling, and circadian clock proteins. Significant changes in the O-GlcNAcylation of DNAJC6AUXI, and PICALM, proteins that are risk factors for PD andor AD respectively, were detected. We compared our study with two key prior O-GlcNAc proteome studies using mouse cerebral tissue and human AD brains. Among those identified to be increased by TG, 15 are also identified to be increased in human AD brains compared to control, including those involved in cytoskeleton, autophagy, chromatin organization and mitochondrial dysfunction. These studies provide insights regarding neurodegenerative diseases therapeutic targets.

Recent Advances in Studying Age-Associated Lipids Alterations and Dietary Interventions in Mammals.

Lipids are involved in a broad spectrum of canonical biological functions, from energy supply and storage by triacylglycerols to membrane formation by sphingolipids, phospholipids and glycolipids. Because of this wide range of functions, there is an overlap between age-associated processes and lipid pathways. Lipidome analysis revealed age-related changes in the lipid composition of various tissues in mice and humans, which were also influenced by diet and gender. Some changes in the lipid profile can be linked to the onset of age-related neurodegenerative diseases like Alzheimers disease. Furthermore, the excessive accumulation of lipid storage organelles, lipid droplets, has significant implications for the development of inflammaging and non-communicable age-related diseases. Dietary interventions such as caloric restriction, time-restrictive eating, and lipid supplementation have been shown to improve pertinent health metrics or even extend life span and thus modulate aging processes.

Curiosity-Based Interventions Increase Everyday Functioning Score But Not Serum BDNF Levels in a Cohort of Healthy Older Adults.

An enriched environment is effective in stimulating learning and memory in animal models as well as in humans. Environmental enrichment increases brain-derived neurotrophic factor (BDNF) in aged rats and reduces levels of Alzheimer-related proteins in the blood, including amyloid-β (Aβ) peptides and misfolded toxic forms of tau. To address whether stimulation of curiosity, which is a form of enrichment, may provide a buffer against Alzheimers disease (AD), we measured levels of biomarkers associated with AD at baseline and after a 6-week intervention in older adults (>65 years of age) randomized to one of three different intervention conditions. Specifically, in this pilot study, we tested the effectiveness of a traditional, structured learning environment compared to a self-motivated learning environment designed to stimulate curiosity. There were no significant differences from baseline to post-intervention in any of the groups for Aβ42Aβ40 ratio or t-tau (total-tau) plasma levels. Serum BDNF levels decreased significantly in the control group. Interestingly, individuals who had the lowest serum BDNF levels at baseline experienced significantly higher increases in BDNF over the course of the 6-week intervention compared to individuals with higher serum BDNF levels at baseline. As expected, older individuals had lower MoCA scores. Years of education correlated negatively with Aβ levels, suggesting a protective effect of education on levels of this toxic protein. ECog scores were negatively correlated with BDNF levels, suggesting that better performance on the ECog questionnaire was associated with higher BDNF levels. Collectively, these findings did not suggest that a 6-week cognitive training intervention focused on curiosity resulted in significant alterations in blood biomarkers but showed interesting correlations between cognitive scores and BDNF levels, further supporting the role of this trophic factor in brain health in older adults.

Neuropathology of Aging in Cats and its Similarities to Human Alzheimers Disease.

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimers disease (AD), including the extracellular accumulation of

Oral-Gut-Brain Axis in Experimental Models of Periodontitis Associating Gut Dysbiosis With Neurodegenerative Diseases.

Periodontitis is considered a non-communicable chronic disease caused by a dysbiotic microbiota, which generates a low-grade systemic inflammation that chronically damages the organism. Several studies have associated periodontitis with other chronic non-communicable diseases, such as cardiovascular or neurodegenerative diseases. Besides, the oral bacteria considered a keystone pathogen,

Prescription Medications and Co-Morbidities in Late Middle-Age are Associated with Greater Cognitive Declines Results from WRAP.

The present study investigated 1) sex differences in polypharmacy, comorbidities, self-rated current health (SRH), and cognitive performance, 2) associations between comorbidities, polypharmacy, SRH, and objective measures of health, and 3) associations of these factors with longitudinal cognitive performance. Analyses included 1039 eligible Wisconsin Registry for Alzheimers Prevention (WRAP) participants who were cognitively unimpaired at baseline and had ≥2 visits with cognitive composites, self-reported health history, and concurrent medication records. Repeated measures correlation (rmcorr) examined the associations between medications, co-morbidities, SRH, and objective measures of health (including LIfestyle for BRAin Health Index (LIBRA), and depression). Linear mixed-effect models examined associations between medications, co-morbidities, and cognitive change over time using a preclinical Alzheimers cognitive composite (PACC3) and cognitive domain z-scores (executive function, working memory, immediate learning, and delayed recall). In secondary analyses, we also examined whether the number of medications interacted with co-morbidities and whether they modified age-related cognitive trajectories. The number of prescribed medications was associated with worse SRH and a higher number of self-reported co-morbidities. More prescribed medications were associated with a faster decline in executive function, and more comorbidities were associated with faster PACC3 decline. Those with a non-elevated number of co-morbidities and medications performed an average of 0.26 SD higher (better) in executive function and an average of 0.18 SD higher on PACC3 than those elevated on both. Associations between medications, co-morbidities, and executive function, and PACC3 suggest that persons with more co-morbidities and medications may be at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers.

Integrative Role of Hyperbaric Oxygen Therapy on Healthspan, Age-Related Vascular Cognitive Impairment, and Dementia.

Growing life expectancy will contribute to the on-going shift towards a world population increasingly comprised of elderly individuals. This demographic shift is associated with a rising prevalence of age-related diseases, among all age-related pathologies it has become crucial to understand the age-associated cognitive changes that remain a major risk factor for the development of vascular cognitive impairment and dementia (VCID). Furthermore, age-related Alzheimers disease and other neurogenerative diseases with vascular etiology are the most prominent contributing factors for the loss of cognitive function observed in aging. Hyperbaric Oxygen Therapy (HBOT) achieves physiologic effects by increasing oxygen tension (PO2), raising oxygen tissue levels, decreasing intracranial pressure and relieving cerebral edema. Many of the beneficial effects of HBOT exert their protective effects at the level of the microcirculation. Furthermore, the microcirculations exquisite pervasive presence across every tissue in the body, renders it uniquely able to influence the local environment of most tissues and organs, including the brain. As such, treatments aimed at restoring aging-induced functional and structural alterations of the cerebral microcirculation may potentially contribute to the amelioration of a range of age-related pathologies including vascular cognitive impairment, Alzheimers disease, and vascular dementias. Despite the presented evidence, the efficacy and safety of HBOT for the treatment of age-related vascular cognitive impairment and dementia remains understudied. The present review aims to examine the existing evidence indicative of a potential therapeutic role for HBOT-induced hyperoxia against age-related cerebromicrovascular pathologies contributing to cognitive impairment, dementia and decreased healthspan in the elderly.

The expanding roles of neuronal nitric oxide synthase (NOS1).

The nitric oxide synthases (NOS EC 1.14.13.39) use L-arginine as a substrate to produce nitric oxide (NO) as a by-product in the tissue microenvironment. NOS1 represents the predominant NO-producing enzyme highly enriched in the brain and known to mediate multiple functions, ranging from learning and memory development to maintaining synaptic plasticity and neuronal development, Alzheimers disease (AD), psychiatric disorders and behavioral deficits. However, accumulating evidence indicate both canonical and non-canonical roles of NOS1-derived NO in several other tissues and chronic diseases. A better understanding of NOS1-derived NO signaling, and identification and characterization of NO-metabolites in non-neuronal tissues could become useful in diagnosis and prognosis of diseases associated with NOS1 expression. Continued investigation on the roles of NOS1, therefore, will synthesize new knowledge and aid in the discovery of small molecules which could be used to titrate the activities of NOS1-derived NO signaling and NO-metabolites. Here, we address the significance of NOS1 and its byproduct NO in modifying pathophysiological events, which could be beneficial in understanding both the disease mechanisms and therapeutics.

Inhibiting BDNF Signaling Upregulates Hippocampal H3K9me3 in a Manner Dependent On

Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimers disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood. In this study, we investigated the role of age-associated stressors on H3K9me3 regulation and examined if changes in H3K9me3 were age dependent. We used cultured hippocampal neurons at 6, 12, and 21 days

A Brief Report on Reviews of Existing Creative Art-Based Interventions in Dementia Care From 2010-2020.

The following brief report provides an overview of previously published reviews in the context of creative arts-based interventions for persons with dementia. A total of 22 review articles were identified and summarized. Next steps are suggested for future studies that may wish to a) develop a new review, or b) create new studies filling in the gaps identified by the authors in this report.

Since its introduction as a genetic model organism,

Friend or Foe Defining the Role of Glutamate in Aging and Alzheimers Disease.

Aging is a naturally occurring decline of physiological processes and biological pathways that affects both the structural and functional integrity of the body and brain. These physiological changes reduce motor skills, executive function, memory recall, and processing speeds. Aging is also a major risk factor for multiple neurodegenerative disorders including Alzheimers disease (AD). Identifying a biomarker, or biomarkers, that signals the transition from physiological to pathological aging would aid in earlier therapeutic options or interventional strategies. Considering the importance of glutamate signaling in synaptic plasticity, motor movement, and cognition, this neurotransmitter serves as a juncture between cognitive health and disease. This article discusses glutamatergic signaling during physiological aging and the pathological changes observed in AD patients. Findings from studies in mouse models of successful aging and AD are reviewed and provide a biological context for this transition. Finally, current techniques to monitor brain glutamate are highlighted. These techniques may aid in elucidating time-point specific therapeutic windows to modify disease outcome.

Geranylgeranylacetone Ameliorates Beta-Amyloid Toxicity and Extends Lifespan

Activation of a cytoprotective cellular pathway known as the heat shock response (HSR) is a promising strategy for the treatment of Alzheimers disease and other neurodegenerative diseases. Geranylgeranylacetone (GGA) is a commonly used anti-ulcer drug in Japan that has been shown to activate the HSR. Here, we establish

Nutrition state of science and dementia prevention recommendations of the Nutrition for Dementia Prevention Working Group.

Observational studies suggest that nutritional factors have a potential cognitive benefit. However, systematic reviews of randomised trials of dietary and nutritional supplements have reported largely null effects on cognitive outcomes and have highlighted study inconsistencies and other limitations. In this Personal View, the Nutrition for Dementia Prevention Working Group presents what we consider to be limitations in the existing nutrition clinical trials for dementia prevention. On the basis of this evidence, we propose recommendations for incorporating dietary patterns and the use of genetic, and nutrition assessment tools, biomarkers, and novel clinical trial designs to guide future trial developments. Nutrition-based research has unique challenges that could require testing both more personalised interventions in targeted risk subgroups, identified by nutritional and other biomarkers, and large-scale and pragmatic study designs for more generalisable public health interventions across diverse populations.

A Histochemical Analysis of Neurofibrillary Tangles in Olfactory Epithelium, a Study Based on an Autopsy Case of Juvenile Alzheimers Disease.

The pathological changes of Alzheimers disease (AD) begin 10-20 years before clinical onset, and it is therefore desirable to identify effective methods for early diagnosis. The nasal mucosa is a target tissue for measuring AD-related biomarkers because the olfactory nerve is the only cranial nerve that is exposed to the external environment. We describe an autopsy case of rapidly advanced juvenile AD (JAD), focusing on the olfactory system. The formation of senile plaques, neurofibrillary tangles (NFTs), and neuropil threads was examined in the temporal cortex, hippocampus, olfactory bulb, and olfactory and respiratory epithelia in the bilateral olfactory clefts. Neurodegenerative changes in the olfactory and respiratory epithelia and the pathological deposition of amyloid β42 (Aβ42) and phosphorylated tau were also examined. As a result, senile plaques, NFTs, and neuropil threads were found in the temporal cortex, hippocampus, and olfactory bulb. NFTs were also found in the olfactory epithelium. Degenerated olfactory cells and their axons stained positive for phosphorylated tau. Supporting cells in the degenerated olfactory epithelium stained positive for Aβ42. In conclusion, pathological biomarkers of AD were expressed in the degenerated olfactory epithelium of this JAD patient. This observation suggests that nasal samples may be useful for the diagnosis of AD.

Post-vaccination infection rates and modification of COVID-19 symptoms in vaccinated UK school-aged children and adolescents A prospective longitudinal cohort study.

We aimed to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection, its effect on COVID-19 presentation, and post-vaccination symptoms in children and adolescents (CA) in the UK during periods of Delta and Omicron variant predominance. In this prospective longitudinal cohort study, we analysed data from 115,775 CA aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2, and described the illness profile of CA with post-vaccination SARS-CoV-2 infection, compared to unvaccinated CA, and post-vaccination side-effects. Between August 5, 2021 and February 14, 2022, 25,971 UK CA aged 12-17 years received one dose of BNT162b2 vaccine. The probability of testing positive for infection diverged soon after vaccination, and was lower in CA with prior SARS-CoV-2 infection. Vaccination reduced proxy-reported infection risk (-80·4% (95% CI -0·82 -0·78) and -53·7% (95% CI -0·62 -0·43) at 14-30 days with Delta and Omicron variants respectively, and -61·5% (95% CI -0·74 -0·44) and -63·7% (95% CI -0·68 -0.59) after 61-90 days). Vaccinated CA who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CA during the Omicron period this was only evident in children aged 12-15 years. Overall disease profile was similar in both vaccinated and unvaccinated CA. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved within few days (3 days in most cases). One dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CA aged 12-17 years. Vaccine protection varied for SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination was generally milder, although unvaccinated CA also had generally mild disease. Overall, vaccination was well-tolerated. UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimers Society, and ZOE Limited.

Physical activity is associated with increased resting-state functional connectivity in networks predictive of cognitive decline in clinically unimpaired older adults.

Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks. rs-fcMRI, amyloid beta (Aβ) positron emission tomography (PET), PA (stepsday × 1 week), and longitudinal cognitive (Preclinical Alzheimers Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used. We used linear and linear mixed-effects regression models to examine the associations between baseline PA and baseline network connectivity and between PA, network connectivity, and longitudinal cognitive performance. Higher PA was associated selectively with greater connectivity in three networks previously associated with cognitive decline (default, salience, left control). This association with network connectivity accounted for a modest portion of PAs effects on Aβ-related cognitive decline. Although other mechanisms are likely present, PA may promote resilience with respect to Aß-related cognitive decline, partly by increasing connectivity in a subset of cognitive networks.

Increased cytokine gene expression and cognition risk associated with androgen deprivation therapy.

Androgen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high-risk, and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment likely develops side-effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses. Gene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced-stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database. A total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine-cytokine signaling with an over representation of cytokine-cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T-cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll-like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL-17A, CCL2, IL-10, IL-6, IL-1RN, LIFLIFR were further validated by quantitative RT-PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen-responsive prostate cancer cells, compared to no-androgen antagonist treatment. Our findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.

Differences in aphasia syndromes between progressive supranuclear palsy-Richardsons syndrome, behavioral variant frontotemporal dementia and Alzheimers dementia.

Language impairments, hallmarks of speechlanguage variant progressive supranuclear palsy, also occur in Richardsons syndrome (PSP-RS). Impaired communication may interfere with daily activities. Therefore, assessment of language functions is crucial. It is uncertain whether the Aachen Aphasia Test (AAT) is practicable in PSP-RS, behavioral variant frontotemporal dementia (bvFTD) and Alzheimers dementia (AD) and language deficits differ in these disorders. 28 PSP-RS, 24 AD, and 24 bvFTD patients were investigated using the AAT and the CERAD-Plus battery. 16-25% of all patients failed in AAT subtests for various reasons. The AAT syndrome algorithm diagnosed amnestic aphasia in 5 (23%) PSP-RS, 7 (36%) bvFTD and 6 (30%) AD patients, Broca aphasia in 1 PSP-RS and 1 bvFTD patient, Wernicke aphasia in 1 bvFTD and 3 (15%) AD patients. However, aphasic symptoms resembled non-fluent primary progressive aphasia in 14 PSP-RS patients. In up to 46% of PSP-RS patients, 61% of bvFTD and 64% of AD patients significant impairments were found in the AAT subtests spontaneous speech, written language, naming, language repetition, language comprehension and the Token subtest. The CERAD-Plus subtest semantic fluency revealed significant impairment in 81% of PSP-RS, 61% of bvFTD, 44% of AD patients, the phonemic fluency subtest in 31, 40 and 31%, respectively. In contrast to bvFTD and AD, severity of language impairment did not correlate with cognitive decline in PSP-RS. In summary, the patterns of aphasia differ between the diagnoses. Local frontal language networks might be impaired in PSP-RS, whereas in AD and bvFTD, more widespread neuropathology might underly language impairment.

Automated semi-quantitative amyloid PET analysis technique without MR images for Alzheimers disease.

Although beta-amyloid (Aβ) positron emission tomography (PET) images are interpreted visually as positive or negative, approximately 10% are judged as equivocal in Alzheimers disease. Therefore, we aimed to develop an automated semi-quantitative analysis technique using Overall, 136 cases of patients administered SUVr calculated by our method and CortexID were highly correlated (R This semi-quantitative analysis technique using

Role of Chemokines in the Development and Progression of Alzheimers Disease.

Alzheimers disease (AD) is a progressive neurogenerative disorder manifested by gradual memory loss and cognitive decline due to profound damage of cholinergic neurons. The neuropathological hallmarks of AD are intracellular deposits of neurofibrillary tangles (NFTs) and extracellular aggregates of amyloid β (Aβ). Mounting evidence indicates that intensified neuroinflammatory processes play a pivotal role in the pathogenesis of AD. Chemokines serve as signaling molecules in immune cells but also in nerve cells. Under normal conditions, neuroinflammation plays a neuroprotective role against various harmful factors. However, overexpression of chemokines initiates disruption of the integrity of the blood-brain barrier, facilitating immune cells infiltration into the brain. Then activated adjacent glial cells-astrocytes and microglia, release massive amounts of chemokines. Prolonged inflammation loses its protective role and drives an increase in Aβ production and aggregation, impairment of its clearance, or enhancement of tau hyperphosphorylation, contributing to neuronal loss and exacerbation of AD. Moreover, chemokines can be further released in response to growing deposits of toxic forms of Aβ. On the other hand, chemokines seem to exert multidimensional effects on brain functioning, including regulation of neurogenesis and synaptic plasticity in regions responsible for memory and cognitive abilities. Therefore, underexpression or complete genetic ablation of some chemokines can worsen the course of AD. This review covers the current state of knowledge on the role of particular chemokines and their receptors in the development and progression of AD. Special emphasis is given to their impact on forming Aβ and NFTs in humans and in transgenic murine models of AD.

The impact of subthreshold levels of amyloid deposition on conversion to dementia in patients with amyloid-negative amnestic mild cognitive impairment.

About 40-50% of patients with amnestic mild cognitive impairment (MCI) are found to have no significant Alzheimers pathology based on amyloid PET positivity. Notably, conversion to dementia in this population is known to occur much less often than in amyloid-positive MCI. However, the relationship between MCI and brain amyloid deposition remains largely unknown. Therefore, we investigated the influence of subthreshold levels of amyloid deposition on conversion to dementia in amnestic MCI patients with negative amyloid PET scans. This study was a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain magnetic resonance imaging, and During the follow-up period, 36% (39107) of patients converted to dementia from amnestic MCI. The dementia converter group displayed increased standardized uptake value ratio (SUVR) values of FBB on PET in the bilateral temporal, parietal, posterior cingulate, occipital, and left precuneus cortices as well as increased global SUVR. Among volume of interests, the left parietal SUVR predicted conversion to dementia with the highest accuracy in the ROC analysis (area under the curve AUC 0.762, P < 0.001). The combination of precuneus, parietal cortex, and FBB composite SUVRs also showed a higher accuracy in predicting conversion to dementia than other models (AUC 0.763). Of the results of ADNI data, the SUVR of the left precuneus SUVR showed the highest AUC (AUC 0.596, P 0.006). Our findings suggest that subthreshold amyloid levels may contribute to conversion to dementia in patients with amyloid-negative amnestic MCI.

MicroRNA-22-3p ameliorates Alzheimers disease by targeting SOX9 through the NF-κB signaling pathway in the hippocampus.

Studies have suggested that many down-regulated miRNAs identified in the brain tissue or serum of Alzheimers disease (AD) patients were involved in the formation of senile plaques and neurofibrillary tangles. Specifically, our previous study revealed that microRNA-22-3p (miR-22-3p) was significantly down-regulated in AD patients. However, the molecular mechanism underlying the down-regulation of miR-22-3p has not been comprehensively investigated. The ameliorating effect of miR-22-3p on apoptosis of the Aβ-treated HT22 cells was detected by TUNEL staining, flow cytometry, and western blotting. The cognition of mice with stereotaxic injection of agomir or antagomir of miR-22-3p was assessed by Morris water maze test. Pathological changes in the mouse hippocampus were analyzed using hematoxylin and eosin (HE) staining, Nissl staining, and immunohistochemistry. Proteomics analysis was performed to identify the targets of miR-22-3p, which were further validated using dual-luciferase reporter analysis and western blotting analysis. The miR-22-3p played an important role in ameliorating apoptosis in the Aβ-treated HT22 cells. Increased levels of miR-22-3p in the mouse hippocampus improved the cognition in mice. Although the miR-22-3p did not cause the decrease of neuronal loss in the hippocampus, it reduced the Aβ deposition. Proteomics analysis revealed Sox9 protein as the target of miR-22-3p, which was verified by the luciferase reporter experiments. Our study showed that miR-22-3p could improve apoptosis and reduce Aβ deposition by acting on Sox9 through the NF-κB signaling pathway to improve the cognition in AD mice. We concluded that miR-22-3p ameliorated AD by targeting Sox9 through the NF-κB signaling pathway in the hippocampus.

Phenazopyridine promotes RPS23RG1Rps23rg1 transcription and ameliorates Alzheimer-associated phenotypes in mice.

Alzheimers disease (AD) is the most common form of dementia with no effective treatment options. A complete elucidation of its underlying molecular mechanisms, including the transcription regulation of genes critically involved in AD, may shed light on new therapeutic development. RPS23RG1 is a newly identified AD-associated gene, whose expression is decreased in AD and restoration can attenuate AD-like phenotypes in animal models. However, the transcription regulation of RPS23RG1 remains unknown. In this study, we explored the promoter of RPS23RG1 and identified its transcription initiation site (TSS) at 1525 bp upstream of the ATG translation start codon. Progressive deletion analysis determined the presence of a negative regulatory region and a positive regulatory region within nucleotide positions 1127 to 1187 and 732 to 1127 relative to the TSS (1), respectively. We conducted a reporter system to screen for compounds that increase RPS23RG1 expression through antagonizing its negative regulatory elements and identified phenazopyridine. Importantly, we demonstrated that phenazopyridine not only promoted RPS23RG1Rps23rg1 expression, but also reduced AD-like pathologies and cognitive impairments in the APPPS1 AD model mice. We also determined a critical negative regulatory domain of RPS23RG1 within nucleotide positions 1177 to 1187 and found that the transcription factor SMAD3 bound to this domain. Inhibition of SMAD3 promoted RPS23RG1 expression. Moreover, phenazopyridine reduced SMAD3 binding to the RPS23RG1 promoter without affecting SMAD3 phosphorylation and nuclear localization. Taken together, our results determine the transcription regulation mechanism of RPS23RG1 and show that phenazopyridine has potential for AD treatment through regulating RPS23RG1 transcription.

Modulation of C5a-C5aR1 signaling alters the dynamics of AD progression.

The complement system is part of the innate immune system that clears pathogens and cellular debris. In the healthy brain, complement influences neurodevelopment and neurogenesis, synaptic pruning, clearance of neuronal blebs, recruitment of phagocytes, and protects from pathogens. However, excessive downstream complement activation that leads to generation of C5a, and C5a engagement with its receptor C5aR1, instigates a feed-forward loop of inflammation, injury, and neuronal death, making C5aR1 a potential therapeutic target for neuroinflammatory disorders. C5aR1 ablation in the Arctic (Arc) model of Alzheimers disease protects against cognitive decline and neuronal injury without altering amyloid plaque accumulation. To elucidate the effects of C5a-C5aR1 signaling on AD pathology, we crossed Arc mice with a C5a-overexpressing mouse (ArcC5a) and tested hippocampal memory. RNA-seq was performed on hippocampus and cortex from Arc, ArcC5aR1KO, and ArcC5a mice at 2.7-10 months and age-matched controls to assess mechanisms involved in each system. Immunohistochemistry was used to probe for protein markers of microglia and astrocytes activation states. ArcC5a mice had accelerated cognitive decline compared to Arc. Deletion of C5ar1 delayed or prevented the expression of some, but not all, AD-associated genes in the hippocampus and a subset of pan-reactive and A1 reactive astrocyte genes, indicating a separation between genes induced by amyloid plaques alone and those influenced by C5a-C5aR1 signaling. Biological processes associated with AD and AD mouse models, including inflammatory signaling, microglial cell activation, and astrocyte migration, were delayed in the ArcC5aR1KO hippocampus. Interestingly, C5a overexpression also delayed the increase of some AD-, complement-, and astrocyte-associated genes, suggesting the possible involvement of neuroprotective C5aR2. However, these pathways were enhanced in older ArcC5a mice compared to Arc. Immunohistochemistry confirmed that C5a-C5aR1 modulation in Arc mice delayed the increase in CD11c-positive microglia, while not affecting other pan-reactive microglial or astrocyte markers. C5a-C5aR1 signaling in AD largely exerts its effects by enhancing microglial activation pathways that accelerate disease progression. While C5a may have neuroprotective effects via C5aR2, engagement of C5a with C5aR1 is detrimental in AD models. These data support specific pharmacological inhibition of C5aR1 as a potential therapeutic strategy to treat AD.

Multidomain trials to prevent dementia addressing methodological challenges.

Multidomain trials to prevent dementia by simultaneously targeting multiple risk factors with non-pharmacological lifestyle interventions show promise. Designing trials to evaluate the efficacy of individual interventions and their combinations is methodologically challenging. Determining the efficacy is, nevertheless, important to individuals, payers, and for resource allocations to support intervention implementation. The central rationale for seminal trials improving cardiovascular health or reducing falls risk in older adults is that multifactorial conditions may be amenable to improvement by simultaneously targeting multiple modifiable risk factors. Similar reasoning underlies lifestyle interventions to reduce dementia risk using combinations of physical exercise, cognitive training, diet, amelioration of vascular-metabolic risk factors, and improving sleep quality. Randomizing individuals with at least two modifiable risk factors to standardly tailored interventions to mitigate their risk factors, versus a comparator arm, will yield an unbiased estimate of the cumulative average effect of modifying more versus fewer risk factors. The between-group difference in the cognitive primary outcome will reflect both the main effects of the mitigated risk factors, as well as their synergistic effects. However, given the positive trial results, there are inherent challenges in quantifying post hoc which components, or combination of components, were responsible for improvements in cognition. Here, we elaborate on these methodological challenges and important considerations in using a standardly tailored design with two arms (one consisting of multidomain interventions tailored to participants risk profiles and another consisting of active control conditions). We compare this approach to fully factorial designs and highlight the disadvantages and advantages of each. We discuss partial solutions, including analytical strategies such as risk reduction scores that measure reductions in the number or severity of risk factors in each study arm. Positive results can support the causal inference that between-group differences in the primary cognitive outcome were due to risk factor modification. Standardly tailored designs are pragmatic and feasible evaluations of multidomain interventions to reduce dementia risk. We propose sensitivity and exploratory analyses of between-group reductions in the severity of risk factors, as a methodology to bolster causal inferences that between-group differences in the primary cognitive outcome are due to the risk factors modified.

Cannabinoid extract in microdoses ameliorates mnemonic and nonmnemonic Alzheimers disease symptoms a case report.

Cannabinoid-based therapy has been shown to be promising and is emerging as crucial for the treatment of cognitive deficits, mental illnesses, and many diseases considered incurable. There is a need to find an appropriate therapy for Alzheimers disease, and cannabinoid-based therapy appears to be a feasible possibility. This report addresses the beneficial effect of cannabinoids in microdoses on improving memory and brain functions of a patient with mild-stage Alzheimers disease. The patient is a 75-year-old white man presenting with main symptoms of memory deficit, spatial and temporal disorientation, and limited daily activity. The experimental therapeutic intervention was carried out for 22 months with microdoses of a cannabis extract containing cannabinoids. Clinical evaluations using Mini-Mental State Examination and Alzheimers Disease Assessment Scale-Cognitive Subscale were performed. Here we provide original evidence that cannabinoid microdosing could be effective as an Alzheimers disease treatment while preventing major side effects. This is an important step toward dissociating cannabinoids health-improving effects from potential narcotic-related limitations.

Apolipoprotein L1 is increased in frontotemporal lobar degeneration post-mortem brain but not in ante-mortem cerebrospinal fluid.

Frontotemporal Dementia (FTD) is caused by frontal-temporal lobar degeneration (FTLD), characterized mainly by brain protein aggregates of tau (FTLD-Tau) or TDP-43 (FTLD-TDP). The clinicopathological heterogeneity makes ante-mortem diagnosis of these pathological subtypes challenging. Our proteomics study showed increased Apolipoprotein L1 (APOL1) levels in CSF from FTD patients, which was prominently expressed in FTLD-Tau. We aimed to understand APOL1 expression in FTLD post-mortem brain tissue and to validate its potential as a CSF biomarker for FTD and its pathological subtypes. APOL1 levels were analyzed in the frontal cortex of FTLD (including FTLD-Tau and FTLD-TDP) and non-demented controls by immunohistochemistry (FTLD total 18 (12 FTLD-Tau and 6 FTLD-TDP) controls 9), western blot (WB), and a novel prototype ELISA (FTLD total 44 (21 FTLD-Tau and 23 FTLD-TDP) controls 9). The association of APOL1 immunoreactivity with phosphorylated Tau (pTau) and TDP-43 (pTDP-43) immunoreactivity was assessed. CSF APOL1 was analyzed in confirmed FTD patients (n 27, including 12 FTLD-Tau and 15 FTLD-TDP) and controls (n 15) using the same ELISA. APOL1 levels were significantly increased in FTLD post-mortem tissue compared to controls as measured by immunohistochemistry, WB, and ELISA. However, no differences between the pathological subtypes were observed. APOL1 immunoreactivity was present in neuronal and glial cells but did not co-localize with pTau or pTDP-43. CSF APOL1 levels were comparable between FTD patients and controls and between pathological subtypes. APOL1 is upregulated in FTLD pathology irrespective of the subtypes, indicating a role of this novel protein in FTD pathophysiology. The APOL1 levels detected in brain tissue were not mirrored in the CSF, limiting its potential as a specific FTD biofluid-based biomarker using our current immunoassay.

Aβ oligomers from human brain impair mossy fiber LTP in CA3 of hippocampus, but activating cAMP-PKA and cGMP-PKG prevents this.

Early cognitive impairment in Alzheimers disease may result in part from synaptic dysfunction caused by the accumulation oligomeric assemblies of amyloid β-protein (Aβ). Changes in hippocampal function seem critical for cognitive impairment in early Alzheimers disease (AD). Diffusible oligomers of Aβ (oAβ) have been shown to block canonical long-term potentiation (LTP) in the CA1 area of hippocampus, but whether there is also a direct effect of oAβ on synaptic transmission and plasticity at synapses between mossy fibers (axons) from the dentate gyrus granule cells and CA3 pyramidal neurons (mf-CA3 synapses) is unknown. Studies in APP transgenic mice have suggested an age-dependent impairment of mossy fiber LTP. Here we report that although endogenous AD brain-derived soluble oAβ had no effect on mossy-fiber basal transmission, it strongly impaired paired-pulse facilitation in the mossy fiber pathway and presynaptic mossy fiber LTP (mf-LTP). Selective activation of both β1 and β2 adrenergic receptors and their downstream cAMPPKA signaling pathway prevented oAβ-mediated inhibition of mf-LTP. Unexpectedly, activation of the cGMPPKG signaling pathway also prevented oAβ-impaired mf-LTP. Our results reveal certain specific pharmacological targets to ameliorate human oAβ-mediated impairment at the mf-CA3 synapse.

A new paradigm for regulation of protein phosphatase 2A function via Src and Fyn kinase-mediated tyrosine phosphorylation.

Protein phosphatase 2A (PP2A) is a major phospho-SerThr phosphatase and a key regulator of cellular signal transduction pathways. While PP2A dysfunction has been linked to human cancer and neurodegenerative disorders such as Alzheimers disease (AD), PP2A regulation remains relatively poorly understood. It has been reported that the PP2A catalytic subunit (PP2Ac) is inactivated by a single phosphorylation at the Tyr307 residue by tyrosine kinases such as v-Src. However, multiple mass spectrometry studies have revealed the existence of other putative PP2Ac phosphorylation sites in response to activation of Src and Fyn, two major Src family kinases (SFKs). Here, using PP2Ac phosphomutants and novel phosphosite-specific PP2Ac antibodies, we show that cellular pools of PP2Ac are instead phosphorylated on both Tyr127 and Tyr284 upon Src activation, and on Tyr284 following Fyn activation. We found these phosphorylation events enhanced the interaction of PP2Ac with SFKs. In addition, we reveal SFK-mediated phosphorylation of PP2Ac at Y284 promotes dissociation of the regulatory Bα subunit, altering PP2A substrate specificity the phosphodeficient Y127284F and Y284F PP2Ac mutants prevented SFK-mediated phosphorylation of Tau at the CP13 (pSer202) epitope, a pathological hallmark of AD, and SFK-dependent activation of ERK, a major growth regulatory kinase upregulated in many cancers. Our findings demonstrate a novel PP2A regulatory mechanism that challenges the existing dogma on the inhibition of PP2A catalytic activity by Tyr307 phosphorylation. We propose dysregulation of SFK signaling in cancer and AD can lead to alterations in PP2A phosphorylation and subsequent deregulation of key PP2A substrates, including ERK and Tau.

Kallikrein 8 A key sheddase to strengthen and stabilize neural plasticity.

Neural networks are modified and reorganized throughout life, even in the matured brain. Synapses in the networks form, change, or disappear dynamically in the plasticity state. The pre- and postsynaptic signaling, transmission, and structural dynamics have been studied considerably well. However, not many studies have shed light on the events in the synaptic cleft and intercellular space. Neural activity-dependent protein shedding is a phenomenon in which (1) presynaptic excitation evokes secretion or activation of sheddases, (2) sheddases are involved not only in cleavage of membrane- or matrix-bound proteins but also in mechanical modulation of cell-to-cell connectivity, and (3) freed activity domains of protein factors play a role in receptor-mediated or non-mediated biological actions. Kallikrein 8neuropsin (KLK8) is a kallikrein family serine protease rich in the mammalian limbic brain. Accumulated evidence has suggested that KLK8 is an important modulator of neural plasticity and consequently, cognition. Insufficiency, as well as excess of KLK8 may have detrimental effects on limbic functions.

Normative Data of Mini-Mental State Examination, Montreal Cognitive Assessment, and Alzheimers Disease Assessment Scale-Cognitive Subscale of Community-Dwelling Older Adults in Taiwan.

Appropriate tools and references are essential for evaluating individuals cognitive levels. This study validated the Taiwan version of the Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-cog) and provided normative data for the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and ADAS-cog in community-dwelling older adults. MMSE, MoCA, and ADAS-cog were administered to 150 nondemented healthy adults aged 55-85 years during 2018-2020 as part of the Northeastern Taiwan Community Medicine Research Cohort. ADAS-cog was translated from the original English version to traditional Chinese with cultural and language considerations in Taiwan. Cronbachs alpha (α) tested the reliability of ADAS-cog, and Pearson correlations examined its external validity using MMSE and MoCA as comparisons. Normative data were generated and stratified by age and education, and the one-way analysis of variance compared scores between age and education groups. Another 20 hospital-acquired participants with cognitive impairment joined the 150 healthy participants. Comparisons in the Clinical Dementia Rating (CDR) tiers tested the discriminability of the tests for different cognitive levels. The area under the receiver operating characteristic curve (AUROC) analyzed the power of ADAS-cog in predicting CDR 0.5 from CDR 0. The Taiwan version of ADAS-cog had fair reliability between items (α 0.727) and good correlations to MMSE (r -0.673, p < 0.001) and MoCA (r -0.746, p < 0.001). The normative data of MMSE, MoCA, and ADAS-cog showed ladder changes with age (p 0.006, 0.001, and 0.437) and education (p < 0.001, <0.001, and <0.001) in the 150 nondemented older adults. Next, in the 170 mixed participants from the communities and the hospital, MMSE, MoCA, and ADAS-cog scores were well differentiable between CDR 0, 0.5, and 1. In addition, ADAS-cog discriminated CDR 0.5 from 0 by an AUROC of 0.827 (p < 0.001). The three structured cognitive tests consistently reflect cognitive levels of healthy older adults. The Taiwan version of ADAS-cog is compatible with MMSE and MoCA to distinguish people with mildly impaired from normal cognition. In addition, this study derived MMSE, MoCA, and ADAS-cog norms tailored to demographic factors. The findings highlight the need for stratification of age and education rather than applying a fixed cutoff for defining normal and abnormal cognition.

Neuropsychiatric Inventory Questionnaire Associated with Cognitive Function, Age, and Duration of Education in Patients with Alzheimers Disease.

Alzheimers disease (AD) is the most common cognitive disease, and behavioral and psychological symptoms of dementia (BPSD) can place a heavy burden on families. The presence of these symptoms related to AD is commonly assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). This study sought to clarify the relationship between scores on the 12-domain NPI-Q and individual factors in patients with AD. Participants were 218 new outpatients with AD at five memory clinics. Cognitive function was assessed using the Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE). We examined which individual factors were associated with the total NPI-Q score and the number of domains. We also examined which domains were associated with the factors identified. A higher total NPI score was significantly associated with lower scores on both cognitive assessments and a longer duration of education. Exhibiting symptoms on a greater number of domains was significantly associated with lower scores on both cognitive assessments, longer duration of education, and advanced age. The nighttime disturbances domain was significantly associated with lower scores on both cognitive assessments and advanced age. The delusions domain was significantly associated with lower education. BPSD may appear more easily with reduced quality of life and ongoing dissatisfaction. Effective individualized services are important for patients with AD, and therefore, we should account for age, cognitive function, and duration of education in the services provided.

Comparative analytical performance of multiple plasma Aβ42 and Aβ40 assays and their ability to predict positron emission tomography amyloid positivity.

This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. Alzheimers Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloidtauneurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aβ) assays using Alzheimers Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aβ4240 predicted amyloid positron emission tomography status better than Aβ42 or Aβ40 alone.

The impacts of health insurance and resource on the burden of Alzheimers disease and related dementias in the world population.

The increasing prevalence of Alzheimers disease and related dementias (ADRD) presents both a burden and an opportunity for intervention. This study aims to estimate the impacts of health insurance and resources on the burden attributed to ADRD. Data were mainly collected from global databases for ADRD. Analysis of variance, Pearson correlation, random-effects, and fixed-effects model analyses were used in this study. Although the current medical expenditures were increasing and out of pocket (OOP) expenditures were declining generally in various countries, the collected global data showed an increased burden of ADRD on patients both physically and economically. Furthermore, health resources were negatively associated with disability-adjusted life years (DALY), death, and years of life lost (YLL), but were otherwise positively associated with years of life lived with disability (YLD). Effective measures should be considered to cope with the rising burden. Meanwhile, there is an urgent call for constructive and sustainable rational plans and global collaboration. We explored how health insurance and resources affect Alzheimers disease and related dementias (ADRD)-related burden. Health insurance and resources were imbalanced among four income level groups. Health insurance and resources may decrease the total ADRD burden primarily from a reduction in death-related burden. Health insurance and resources may increase disability-related burden.

Artificial intelligence in ophthalmology an insight into neurodegenerative disease.

The aging world population accounts for the increasing prevalence of neurodegenerative diseases such as Alzheimers and Parkinsons which carry a significant health and economic burden. There is therefore a need for sensitive and specific noninvasive biomarkers for early diagnosis and monitoring. Advances in retinal and optic nerve multimodal imaging as well as the development of artificial intelligence deep learning systems (AI-DLS) have heralded a number of promising advances of which ophthalmologists are at the forefront. The association among retinal vascular, nerve fiber layer, and macular findings in neurodegenerative disease is well established. In order to optimize the use of these ophthalmic parameters as biomarkers, validated AI-DLS are required to ensure clinical efficacy and reliability. Varied image acquisition methods and protocols as well as variability in neurogenerative disease diagnosis compromise the robustness of ground truths that are paramount to developing high-quality training datasets. In order to produce effective AI-DLS for the diagnosis and monitoring of neurodegenerative disease, multicenter international collaboration is required to prospectively produce large inclusive datasets, acquired through standardized methods and protocols. With a uniform approach, the efficacy of resultant clinical applications will be maximized.

Studying Unconventional Secretion of Misfolded Proteins in Cultured Cells and Primary Neurons.

Protein misfolding poses a significant threat to the fitness of eukaryotic cells, particularly for neurons facing environmental stress. To effectively triage and remove defective and unwanted proteins, cells have evolved diverse protein quality control (PQC) mechanisms relying on proteasome- and endolysosome-mediated degradation systems. Defects in PQC functions are linked to various human diseases including many aging-associated neurodegenerative diseases. Misfolding-associated protein secretion (MAPS) is a recently reported PQC mechanism that eliminates misfolded cytosolic proteins by an unconventional secretory pathway using an endo-vesiclular network. This process implicates DNAJC5, a chaperone that escorts misfolded cargos to intracellular vesicles to facilitate their secretion. Cargos of DNAJC5 include Parkinsons and Alzheimers disease-associated proteins known to undergo cell-to-cell transmission during disease progression. Thus, elucidating how these proteins are secreted may reveal novel therapeutic targets for these diseases. Here we describe a collection of methods used to detect either the basal or induced secretion of misfolded proteins from cell lines and cultured primary neurons.

Differential spatial distribution of white matter lesions in Parkinsons and Alzheimers diseases and cognitive sequelae.

White Matter Lesions (WML) are a radiological finding common in aged subjects. We explored the impact of WML on underlying neurodegenerative processes. We focused on the impact of WML on two neurodegenerative diseases with different pathology. In this cross-sectional study of 137 subjects (78 female, 59 men, mean age 67.2 43-87 years), we compared WML in healthy controls (HC n 55), patients with Alzheimers disease and amnestic Mild Cognitive Impairment (aMCI), and Parkinsons disease patients with normal cognition and with MCI. Subjects with AD and aMCI were treated as one group (n 40), subjects with PD and PDMCI were another group (n 42). MRI T2FLAIR sequences were analyzed. WML were divided into periventricular (pWML) or subcortical (sWML) depending on their distance from the ventricles. Subjects from the AD aMCI group, had a significantly greater volume of WML than both HC and the PD PDMCI group. The volume of WML was greater in the PD PDMCI than in HC but the difference was not significant. In AD aMCI subjects, sWML and not pWML were related to a decrease in global cognitive functioning despite greater volume of pWML. In PD PDMCI, pWML correlate with decline in executive functions and working memory. In HC, pWML correlated with the multidomain decrease corresponding with the aging. This points to a difference between normal aging and pathological aging due to AD and PD brain pathology. The WML location together with underlying disease related neurodegeneration may play a role in determining the effect of WML on cognition. Our results suggest that the impact of WML is not uniform in all patients rather, their volume, location and cognitive effect may be disease-specific.

Cryo-EM structures of prion protein filaments from Gerstmann-Sträussler-Scheinker disease.

Prion protein (PrP) aggregation and formation of PrP amyloid (APrP) are central events in the pathogenesis of prion diseases. In the dominantly inherited prion protein amyloidosis known as Gerstmann-Sträussler-Scheinker (GSS) disease, plaques made of PrP amyloid are present throughout the brain. The c.593t > c mutation in the prion protein gene (PRNP) results in a phenylalanine to serine amino acid substitution at PrP residue 198 (F198S) and causes the most severe amyloidosis among GSS variants. It has been shown that neurodegeneration in this disease is associated with the presence of extracellular APrP plaques and neuronal intracytoplasmic Tau inclusions, that have been shown to contain paired helical filaments identical to those found in Alzheimer disease. Using cryogenic electron microscopy (cryo-EM), we determined for the first time the structures of filaments of human APrP, isolated post-mortem from the brain of two symptomatic PRNP F198S mutation carriers. We report that in GSS (F198S) APrP filaments are composed of dimeric, trimeric and tetrameric left-handed protofilaments with their protomers sharing a common protein fold. The protomers in the cross-β spines consist of 62 amino acids and span from glycine 80 to phenylalanine 141, adopting a previously unseen spiral fold with a thicker outer layer and a thinner inner layer. Each protomer comprises nine short β-strands, with the β1 and β8 strands, as well as the β4 and β9 strands, forming a steric zipper. The data obtained by cryo-EM provide insights into the structural complexity of the PrP filament in a dominantly inherited human PrP amyloidosis. The novel findings highlight the urgency of extending our knowledge of the filaments structures that may underlie distinct clinical and pathologic phenotypes of human neurodegenerative diseases.

Parkinsons Disease and the Criminal Justice System.

Parkinsons disease is the worlds second most common neurodegenerative disorder, and its incidence is growing. This editorial reviews the current state of knowledge about Parkinsons disease, its causes, its treatment and the symptomatology that is relevant to the administration of criminal justice. It identifies that, in conjunction with comorbidities, the disease can result in unfitness to stand trial, soundly based pleas of insanitymental impairment and, in particular, can have a significant effect on the sentencing of offenders. It argues that with the ageing of the modern jail population, the incidence of Parkinsons disease provides a strong justification for the creation of alternative health care approaches that can provide suitable custodial services for those with conditions such as Parkinsons disease, Alzheimers disease and a variety of forms of dementia.

Aspartic Acid-Modified Phospholipids Regulate Cell Response and Rescue Memory Deficits in APPPS1 Transgenic Mice.

Misfolding and accumulation of amyloid-β (Aβ) to form senile plaques are the main neuropathological signatures of Alzheimers disease (AD). Decreasing Aβ production, inhibiting Aβ aggregation, and clearing Aβ plaques are thus considered an important strategy for AD treatment. However, numerous drugs cannot enter the AD clinical trials due to unsatisfactory biocompatibility, poor blood-brain barrier penetration, little biomarker impact, andor low therapeutic indicators. Here, a pair of chiral aspartic acid-modified 1,2-dipalmitoyl-

Incompleteness features in the descriptive discourse of Chinese elders with and without

Alzheimers disease (AD) can manifest itself with prominent language dysfunction. Incompleteness in discourse refers to the lack of indispensable sentence-constructing elements that hinder communication fluency and accuracy. The current study investigates how the pattern of incompleteness is associated with the descriptive discourse produced by elders without AD and those with different stages of AD. The Chinese discourse samples were collected from the picture description of 40 elders with mild probable AD (Mini-Mental State Examination (MMSE) 21-26, Montreal Cognitive Assessment Scale-Basic (MoCA-B) 15-19), 40 elders with moderate probable AD (MMSE 11-20, MoCA-B 10-14), and 40 controls (MMSE 26-29, MoCA-B 24-29). The total production of incomplete sentences and six incompleteness features were examined. The Mild AD, Moderate AD, and Control groups differed in the total output of the incomplete sentence. Group differences also emerged in four incompleteness features missing subject, missing predicate, missing object, and missing functional word. The Moderate AD group differed from the Mild AD group with respect to most significant features, while Mild AD and Control groups were very similar. The results suggested that AD impairs the sentence construction ability of Chinese elders, especially at the later stage. These statistically significant differences between the groups might provide some references when diagnosing the risk and possibility of cognitive impairment of Chinese elders, facilitating the design of clinical evaluation or screening for probable AD.

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 420 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 821 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 242 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results these involved immune response, neuronal constituents, and olfactorytaste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Tau-binding protein PRMT8 facilitates vacuole degeneration in the brain.

Amyloid-β and tau pathologies are important factors leading to neurodegeneration in Alzheimers disease (AD) however, the molecular mechanisms that link these pathologies remain unclear. Assuming that important though as yet unidentified factors inhibitaccelerate tau pathology and neuronal cell death under amyloid pathology, we sought to isolate and identify tau-interacting proteins from mouse brains with or without amyloid pathology. Among the proteins that were identified, we focused on protein arginine methyltransferase 8 (PRMT8), which interacts with tau specifically in the absence of amyloid pathology. To investigate the role of PRMT8 in the pathogenesis of AD, we conducted Prmt8 gene deletion and overexpression experiments in AppNL-G-FMAPT double knock-in mice and analysed the resulting pathological alterations. PRMT8-knockout did not alter the AD pathology in double knock-in mice, whereas PRMT8-overexpression promoted tau phosphorylation, neuroinflammation and vacuole degeneration. To evaluate if such a PRMT8-induced vacuole degeneration depends on tau pathology, PRMT8 was overexpressed in tau-KO mice, which were consequently found to exhibit vacuole degeneration. In addition, proteomic analyses showed that PRMT8 overexpression facilitated the arginine methylation of vimentin. Abnormal protein methylation could be involved in PRMT8-induced brain pathologies. Taken together, PRMT8 may play an important role in the formation of tau pathology and vacuole degeneration.

Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β.

The progression of neurodegenerative disorders can lead to impaired neurotransmission however, the role of pathogenic factors associated with these diseases and their impact on the structures and functions of neurotransmitters have not been clearly established. Here we report the discovery that conformational and functional changes of a native neuropeptide, somatostatin (SST), occur in the presence of copper ions, metal-free amyloid-β (Aβ) and metal-bound Aβ (metal-Aβ) found as pathological factors in the brains of patients with Alzheimers disease. These pathological elements induce the self-assembly of SST and, consequently, prevent it from binding to the receptor. In the reverse direction, SST notably modifies the aggregation profiles of Aβ species in the presence of metal ions, attenuating their cytotoxicity and interactions with cell membranes. Our work demonstrates a loss of normal function of SST as a neurotransmitter and a gain of its modulative function against metal-Aβ under pathological conditions.

Identification and validation of Alzheimers disease-related metabolic brain pattern in biomarker confirmed Alzheimers dementia patients.

Metabolic brain biomarkers have been incorporated in various diagnostic guidelines of neurodegenerative diseases, recently. To improve their diagnostic accuracy a biologically and clinically homogeneous sample is needed for their identification. Alzheimers disease-related pattern (ADRP) has been identified previously in cohorts of clinically diagnosed patients with dementia due to Alzheimers disease (AD), meaning that its diagnostic accuracy might have been reduced due to common clinical misdiagnosis. In our study, we aimed to identify ADRP in a cohort of AD patients with CSF confirmed diagnosis, validate it in large out-of-sample cohorts and explore its relationship with patients clinical status. For identification we analyzed 2-

Targeting Angiogenesis via Resolution of Inflammation.

Angiogenesis, the growth of new blood vessels, plays a critical role in tissue repair and regeneration, as well as in cancer. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving mediators (SPMs), including resolvins. Angiogenesis and the resolution of inflammation are critical interdependent processes. Disrupted inflammation resolution can accelerate tumor growth, which is angiogenesis-dependent. SPMs, including resolvins and lipoxins, inhibit physiologic and pathological angiogenesis at nanogram concentrations. The failure of resolution of inflammation is an emerging hallmark of angiogenesis-dependent diseases including arthritis, psoriasis, diabetic retinopathy, age-related macular degeneration, inflammatory bowel disease, atherosclerosis, endometriosis, Alzheimers disease, and cancer. Whereas therapeutic angiogenesis repairs tissue damage (e.g., limb ischemia), inhibition of pathological angiogenesis suppresses tumor growth and other non-neoplastic diseases such as retinopathies. Stimulation of resolution of inflammation via pro-resolving lipid mediators promotes the repair of tissue damage and wound healing, accelerates tissue regeneration, and inhibits cancer. Here we provide an overview of the mechanisms of cross talk between angiogenesis and inflammation resolution in chronic inflammation-driven diseases. Stimulating the resolution of inflammation via pro-resolving lipid mediators has emerged as a promising new field to treat angiogenic diseases.

Aptamer-Functionalized Carbon Nanotube Field-Effect Transistor Biosensors for Alzheimers Disease Serum Biomarker Detection.

Blood-biomarker-based tests are highly important for the early clinical diagnosis of Alzheimers disease (AD) and the treatment and care of AD patients, but the complex serum environment and extremely low abundance of AD blood protein biomarkers present challenges. Nanomaterials are promising for constructing highly sensitive transistor-based biosensors due to their small size. However, such biosensors are difficult to fabricate on a large scale and suffer from the lack of combined optimization of reproducibility and sensitivity in complex physiological fluids. In this work, field-effect transistor (FET) biosensors based on highly uniform semiconducting carbon nanotube (CNT) thin films are mass produced to achieve highly sensitive and selective detection of the AD core blood biomarkers of β-amyloid (Aβ). The combination of the mass-produced CNT FET sensors and oligonucleotide aptamers as efficient bioreceptors enables reliable and reproducible sub-femtomolar detection in full human serum for Aβ

Exploring Heterogeneous Dynamical Environment around an Ensemble of Aβ

Exploring the conformational properties of amyloid β (Aβ) peptides and the role of solvent (water) in guiding the dynamical environment at their interfaces is crucial for microscopic understanding of Aβ misfolding, which is involved in causing the most common neurodegenerative disorder, i.e., Alzheimers disease. While numerous studies in the past have emphasized examining the conformational states of Aβ peptides, the role of water has not received much attention. Here, we have performed all-atom molecular dynamics simulations of several full-length Aβ

Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice.

Neurodegenerative diseases involving pathological tau protein aggregation are collectively known as tauopathies and include Alzheimers disease and Picks disease. Recent studies show that the intake of tryptophan-tyrosine (Trp-Tyr)-related β-lactopeptides, including β-lactolin, attenuates cognitive decline in the elderly and prevents the amyloid pathology in mouse models of Alzheimers disease. However, the effects of Trp-Tyr-related β-lactopeptides on tau-related pathology have not been investigated. In the present study, we examined the effects of Trp-Tyr dipeptide intake on tauopathy in PS19 transgenic mice, a well-established tauopathy model. Intake of Trp-Tyr dipeptide improved the behavioral deficits observed in the open field test, prevented tau phosphorylation, and increased the dopamine turnover and synaptophysin expression in the frontal cortex. Levels of short-chain fatty acids in the cecum were lower in PS19 mice than those in wild-type mice and were increased by treatment with Trp-Tyr dipeptide. In addition, intake of Trp-Tyr dipeptide extended the lifespan of PS19 mice. These findings suggest that the intake of Trp-Tyr-related peptides improves tauopathy symptoms, resulting in improvements in behavioral deficits and longevity. Hence, the intake of Trp-Tyr-related peptides, including β-lactolin, may be beneficial for preventing dementia.

TREM2-induced activation of microglia contributes to synaptic integrity in cognitively intact aged individuals with Alzheimers neuropathology.

The existence of individuals who remain cognitively intact despite presenting histopathological signs of Alzheimers disease (AD), here referred to as Nondemented with AD neuropathology (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. Exposed phosphatidylserine (ePS) represents a neuronal eat-me signal involved in microglial-mediated phagocytosis of damaged synapses. A possible mediator of this process is TREM2, a microglial surface receptor activated by ligands including PS. Based on TREM2 role in the scavenging function of microglia, we hypothesize that an efficient microglial phagocytosis of damaged synapses underlies synaptic resilience in NDAN, thus protecting from memory deficits. Using immunofluorescence microscopy, we performed a comparative study of human post-mortem frontal cortices of aged-matched, AD and NDAN individuals. We studied the distribution of activated microglia (IBA1, IBA1

The design and conduct of a pragmatic cluster randomized trial of an advance care planning program for nursing home residents with dementia.

A significant number of people with Alzheimers disease or related dementia diagnoses will be cared for in nursing homes near the end of life. Advance care planning (ACP), the process of eliciting and documenting patient-centered preferences for care, is considered essential to providing high quality care for this population. Nursing homes are currently required by regulations to offer ACP to residents and families, but no training requirements exist for nursing home staff, and approaches to fulfilling this regulatory and ethical responsibility vary. As a result, residents may receive care inconsistent with their goals, such as unwanted hospitalizations. Pragmatic trials offer a way to develop and test ACP in real-world settings to increase the likelihood of adoption of sustainable best practices. The Aligning Patient Preferences-a Role Offering Alzheimers patients, Caregivers, and Healthcare Providers Education and Support (APPROACHES) project is designed to pragmatically test and evaluate a staff-led program in 137 nursing homes (68 intervention, 69 control) owned by two nursing home corporations. Existing nursing home staff receive standardized training and implement the ACP Specialist program under the supervision of a corporate lead. The primary trial outcome is the annual rate of hospital transfers (admissions and emergency department visits). Consistent with the spirit of a pragmatic trial, study outcomes rely on data already collected for quality improvement, clinical, or billing purposes. Configurational analysis will also be performed to identify conditions associated with implementation. Partnerships with large corporate companies enable the APPROACHES trial to rely on corporate infrastructure to roll out the intervention, with support for a corporate implementation lead who is charged with the initial introduction and ongoing support for nursing home-based ACP Specialists. These internal champions connect the project with other company priorities and use strategies familiar to nursing home leaders for the initiation of other programs. Standardized data collection across nursing homes also supports the conduct of pragmatic trials in this setting. Many interventions to improve care in nursing homes have failed to demonstrate an impact or, if successful, maintain an impact over time. Pragmatic trials, designed to test interventions in real-world contexts that are evaluated through existing data sources collected routinely as part of clinical care, are well suited for the nursing home environment. A robust program that increases access to ACP for nursing home residents has the potential to increase goal-concordant care and is expected to reduce hospital transfers. If successful, the ACP Specialist Program will be primed for rapid translation into nursing home practice to reduce unwanted, burdensome hospitalizations and improve the quality of care for residents with dementia.

Golgi-Targeted Fluorescent Probe for Imaging NO in Alzheimers Disease.

Nitric oxide (NO) is a crucial neurotransmitter participating in many biological processes via nitrosylation reaction. NO produced in diverse subcellular regions also regulates the function of cells in different manners. A Golgi apparatus is rich in nitric oxide synthase and may serve as a potential therapeutic target for Alzheimers disease (AD). However, due to the lack of an effective tool, it is difficult to reveal the relationship between Golgi-NO and AD. Herein, we report Golgi-NO as the first Golgi-targeted fluorescent probe for sensing and imaging NO in the Golgi apparatus. The probe is designed and synthesized by incorporating 4-sulfamoylphenylamide as a Golgi-targeted moiety to 6-carboxyrhodamine B, generating a fluorophore of Golgi-RhB with modifiable carboxyl, which is then combined with the NO recognition moiety of

Ignoring the Experts Implications of the FDAs Aduhelm Approval.

In early June 2021, the U.S. Food and Drug Administration (FDA) granted Accelerated Approval to Aducanumab (Aduhelm) for treating Alzheimers disease. The decision was immediately engulfed in controversy because the agency ignored the Scientific Drugs Advisory Committees unanimous recommendation not to approve the drug. The FDA granted the approval based on Aduhelms ability to lower beta-amyloid levels. However, the agency had not previously indicated this as a surrogate clinical end for the trial, and its own scientific analysis failed to show that amyloid changes correlate with cognitive or functional changes for Alzheimers patients. This decision sets dangerous precedent and has the potential to transform the approval process for new drugs including, but not limited to, those meant to treat Alzheimers.

Dyhidro-β-agarofurans natural and synthetic as acetylcholinesterase and COX inhibitors interaction with the peripheral anionic site (AChE-PAS), and anti-inflammatory potentials.

In order to find molecules of natural origin with potential biological activities, we isolate and synthesise compounds with agarofuran skeletons (epoxyeudesmanes). From the seeds of

Social class and the risk of dementia A systematic review and meta-analysis of the prospective longitudinal studies.

The association between belonging to a disadvantaged socio-economic status or social class and health outcomes has been consistently documented during recent decades. However, a meta-analysis quantifying the association between belonging to a lower social class and the risk of dementia has yet to be performed. In the present work, we sought to summarise the results of prospective, longitudinal studies on this topic. We conducted a systematic review and meta-analysis of prospective, longitudinal studies measuring the association between indicators of social class and the risk of all-causeAlzheimers dementia. The search was conducted in four databases (Medline, Embase, Web of Science and PsychInfo). Inclusion criteria for this systematic review and meta-analysis were (a) longitudinal prospective study, (b) aged ⩾60 years at baseline, (c) issued from the general population, (d) no dementia at baseline and (e) mention of social class as exposure. Exclusion criteria were (a) study of rare dementia types (e.g. frontotemporal dementia), (b) abstract-only papers and (c) articles without full text available. The Newcastle-Ottawa scale was used to assess the risk of bias in individual studies. We calculated the overall pooled relative risk of dementia for different social class indicators, both crude and adjusted for sex, age and the year of the cohort start. Out of 4548 screened abstracts, 15 were included in the final analysis (76,561 participants, mean follow-up 6.7 years (2.4-25 years), mean age at baseline 75.1 years (70.6-82.1 years), mean percentage of women 58%). Social class was operationalised as levels of education, occupational class, income level, neighbourhood disadvantage and wealth. Education (relative risk (RR)2.48 confidence interval (CI) 1.71-3.59) and occupational class (RR2.09 CI 1.18-3.69) but not income (RR1.28 CI 0.81-2.04) were significantly associated with the risk of dementia in the adjusted model. Some of the limitations of this study are the inclusion of studies predominantly conducted in high-income countries and the exclusion of social mobility in our analysis.

Effects of Catalpol on Alzheimers Disease and Its Mechanisms.

Alzheimers disease (AD) is a degenerative disease of the central nervous system characterized by memory loss and cognitive dysfunction. With the increasing aging of the population, the incidence of AD and the number of patients are also increasing year by year, causing more and more heavy burdens to the family and society. Catalpol, an iridoid glycoside compound, is one of the main active components of

Caesalpinbondin A, a Novel Diterpenoid Lactone With an Unprecedented Carbon Skeleton from the Seeds of

One novel diterpenoid lactone named caesalpinbondin A (

The Role of Brain-Derived Neurotrophic Factor Signaling in Central Nervous System Disease Pathogenesis.

Recent studies have found abnormal levels of brain-derived neurotrophic factor (BDNF) in a variety of central nervous system (CNS) diseases (e.g., stroke, depression, anxiety, Alzheimers disease, and Parkinsons disease). This suggests that BDNF may be involved in the pathogenesis of these diseases. Moreover, regulating BDNF signaling may represent a potential treatment for such diseases. With reference to recent research papers in related fields, this article reviews the production and regulation of BDNF in CNS and the role of BDNF signaling disorders in these diseases. A brief introduction of the clinical application status of BDNF is also provided.

Copper chelating cyclic peptidomimetic inhibits Aβ fibrillogenesis.

Misfolding of the amyloid-β peptide (Aβ) and its subsequent aggregation into toxic oligomers is one of the leading causes of Alzheimers disease (AD). As a therapeutic approach, cyclic peptides have been modified in many ways and developed as a potential class of amyloid aggregation inhibitors. Head-to-tail cyclic peptides with alternating d, l amino acids inhibit amyloid aggregation significantly. On the other hand, excess deposition of copper, iron, and zinc enhances amyloid aggregation. Dysregulation of these metal ions in the brain triggers aggregation by binding to the Aβ peptide. Therefore, specific metal chelators have been developed for disrupting the Aβ-metal complex, thereby reducing toxicity and restoring metal ion homeostasis. Herein, we report the development of a head-to-tail cyclic peptidomimetic with a copper chelating ligand attached. The designed peptidomimetic inhibits amyloid aggregation significantly in a two-fold molar ratio to the Aβ peptide, as confirmed by the thioflavin T (ThT) fluorescence assay, dynamic light scattering (DLS), transmission electron microscopy (TEM), and Congo-red stained birefringence studies. The chelating ligand attached to the cyclic peptide binds efficiently to Cu

Inhibition of MARK4 by serotonin as an attractive therapeutic approach to combat Alzheimers disease and neuroinflammation.

Mitogen-activated protein kinases (MAPKs) govern various cellular programs and crucial intermediate pathways in signaling. Microtubule affinity-regulating kinase 4 (MARK4) is a part of the kinase family recognized for actively phosphorylating neural microtubule-associated proteins (MAPs) like MAP2, MAP4 and most importantly, tau. The SerThr kinase MARK4 overexpression is associated with various life-threatening conditions such as neurodegenerative disorders, diabetic neuropathy, and cancer. Functionally, MARK4 is correlated with many important signaling cascades and transcription factors contributing to neurodegeneration and cancer onset and progression. Serotonin is a key molecule associated with regulating mood, stress, and various behavioral aspects. Low serotonin levels promote the progression of neurological and psychotic disorders, which is also a consequence of tau accumulation. MARK4 being a major contributor to phosphorylating tau, leading to its accumulation, and contributing to tauopathy, is targeted for inhibition by serotonin. The study deals with the inhibition of MARK4 by serotonin using combined computational and experimental studies. The results presented in this paper provide strong evidence for the direct physical binding of serotonin to recombinant MARK4 and subsequent inhibition of its kinase activity. In addition, we have performed molecular docking, followed by 100 ns MD simulations of MARK4 in the presence of serotonin, to estimate the stability of the protein-ligand complex. Since MARK4 is a potential drug target and can be exploited for drug design and discovery for cancer and neurodegenerative disorders, the results presented here are of interest and may be further exploited for Alzheimers disease (AD) and other neurodegenerative diseases.

Mitochondria in neurodegeneration.

The brain is one of the most energetically demanding tissues in the human body, and mitochondrial pathology is strongly implicated in chronic neurodegenerative diseases. In contrast to acute brain injuries in which bioenergetics and cell death play dominant roles, studies modeling familial neurodegeneration implicate a more complex and nuanced relationship involving the entire mitochondrial life cycle. Recent literature on mitochondrial mechanisms in Parkinsons disease, Alzheimers disease, frontotemporal dementia, Huntingtons disease, and amyotrophic lateral sclerosis is reviewed with an emphasis on mitochondrial quality control, transport and synaptodendritic calcium homeostasis. Potential neuroprotective interventions include targeting the mitochondrial kinase PTEN-induced kinase 1 (PINK1), which plays a role in regulating not only multiple facets of mitochondrial biology, but also neuronal morphogenesis and dendritic arborization.

Vascular and microstructural markers of cognitive pathology.

Arterial stiffness may play a role in the development of dementia through poorly understood effects on brain microstructural integrity and perfusion. We examined markers of arterial stiffness (carotid-femoral pulse wave velocity cfPWV) and elevated systolic blood pressure (SBP) in relation to cognitive function and brain magnetic resonance imaging macrostructure (gray matter GM and white matter WM volumes), microstructure (diffusion based free water FW and fractional anisotropy FA), and cerebral blood flow (CBF) in WM and GM in models adjusted for age, race, sex, education, and apolipoprotein E ε4 status. Among 460 participants (70 ± 8 years 44 dementia, 158 mild cognitive impairment, 258 normal cognition), higher cfPWV and SBP were independently associated with higher FW, higher WM hyperintensity volume, and worse cognition (global and executive function). Higher SBP alone was significantly associated with lower WM and GM CBF. Arterial stiffness is associated with impaired WM microstructure and global and executive cognitive function.

Retinal arteriolar parameters as a surrogate marker of intracranial vascular pathology.

Development of novel diagnostic tools is a top research priority in vascular dementia. A major obstacle is the lack of a simple, non-invasive method to visualize cerebral arteriolar walls in vivo. Retinal arterioles offer a window into the cerebral circulation. MWT and WLR were higher in CSVD, associated with severity of vascular white matter lesions, and correlated with magnetic resonance imaging-based intracranial arteriolosclerosis score. WLR correlated with gray and white matter volume and differentiated asymptomatic sporadic CSVD from HC (area under the curve 0.82). I-bRAVO is a rapid, non-invasive tool. MWT and WLR were associated with imaging markers of CSVD and could contribute to early identification of sporadic CSVD.

Classification of Transgenic Mice by Retinal Imaging Using SVMS.

Alzheimers disease is the neuro disorder which characterized by means of Amyloid-

Mechanism of Neural Regeneration Induced by Natural Product LY01 in the 5×FAD Mouse Model of Alzheimers Disease.

Modeling Neurodegenerative Diseases Using

The human brain is a complex organ composed of many different types of cells interconnected to create an organized system able to efficiently process information. Dysregulation of this delicately balanced system can lead to the development of neurological disorders, such as neurodegenerative diseases (NDD). To investigate the functionality of human brain physiology and pathophysiology, the scientific community has been generated various research models, from genetically modified animals to two- and three-dimensional cell culture for several decades. These models have, however, certain limitations that impede the precise study of pathophysiological features of neurodegeneration, thus hindering therapeutical research and drug development. Compartmentalized microfluidic devices provide

Evaluation of Feature Selection for Alzheimers Disease Diagnosis.

Accurate recognition of patients with Alzheimers disease (AD) or mild cognitive impairment (MCI) is important for the subsequent treatment and rehabilitation. Recently, with the fast development of artificial intelligence (AI), AI-assisted diagnosis has been widely used. Feature selection as a key component is very important in AI-assisted diagnosis. So far, many feature selection methods have been developed. However, few studies consider the stability of a feature selection method. Therefore, in this study, we introduce a frequency-based criterion to evaluate the stability of feature selection and design a pipeline to select feature selection methods considering both stability and discriminability. There are two main contributions of this study (1) It designs a bootstrap sampling-based workflow to simulate real-world scenario of feature selection. (2) It develops a decision graph to determine the optimal combination of supervised and unsupervised feature selection both considering feature stability and discriminability. Experimental results on the ADNI dataset have demonstrated the feasibility of our method.

Differential Patterns of Domain-Specific Cognitive Complaints and Awareness Across the Alzheimers Disease Spectrum.

REPS1 as a Potential Biomarker in Alzheimers Disease and Vascular Dementia.

Vascular dementia (VD) and Alzheimers disease (AD) are common types of dementia for which no curative therapies are known. In this study, we identified hub genes associated with AD and VD in order to explore new potential therapeutic targets. Genes differentially expressed in VD and AD in all three datasets (GSE122063, GSE132903, and GSE5281) were identified and used to construct a protein-protein interaction network. We identified 10 modules containing 427 module genes in AD and VD. Module genes showing an area under the diagnostic curve > 0.60 for AD or VD were used to construct a least absolute shrinkage and selection operator model and were entered into a support vector machine-recursive feature elimination algorithm, which identified REPS1 as a hub gene in AD and VD. Furthermore, REPS1 was associated with activation of pyruvate metabolism and inhibition of Ras signaling pathway. Module genes, together with differentially expressed microRNAs from the dataset GSE46579, were used to construct a regulatory network. REPS1 was predicted to bind to the microRNA hsamiR5701. Single-sample gene set enrichment analysis was used to explore immune cell infiltration, which suggested a negative correlation between REPS1 expression and infiltration by plasmacytoid dendritic cells in AD and VD. In conclusion, our results suggest core pathways involved in both AD and VD, and they identify REPS1 as a potential biomarker of both diseases. This protein may aid in early diagnosis, monitoring of treatment response, and even efforts to prevent these debilitating disorders.

Selective Serotonin Reuptake Inhibitor-Treatment Does Not Show Beneficial Effects on Cognition or Amyloid Burden in Cognitively Impaired and Cognitively Normal Subjects.

Preclinical studies indicate that selective serotonin reuptake inhibitors (SSRI) have beneficial effects on Alzheimer-related pathologies. Therefore, the aim of this study was to evaluate the influence of SSRI-treatment on amyloid burden in

Photo-Oxygenation as a New Therapeutic Strategy for Neurodegenerative Proteinopathies by Enhancing the Clearance of Amyloid Proteins.

Alzheimer disease (AD) is associated with the aggregation of two amyloid proteins tau and amyloid-β (Aβ). The results of immunotherapies have shown that enhancing the clearance and suppressing the aggregation of these two proteins are effective therapeutic strategies for AD. We have developed photocatalysts that attach oxygen atoms to Aβ and tau aggregates

Most Pathways Can Be Related to the Pathogenesis of Alzheimers Disease.

Alzheimers disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association

The Periodontal Pathogen

Alzheimers Disease (AD) is the most common form of dementia in older adults and has a devastating impact on the patients quality of life, which creates a significant socio-economic burden for the affected individuals and their families. In recent years, studies have identified a relationship between periodontitis and AD. Periodontitis is an infectiousinflammatory disease that destroys the supporting periodontal structure leading to tooth loss. Dysbiosis of the oral microbiome plays a significant role in the onset and development of periodontitis exhibiting a shift to overgrowth of pathobionts in the normal microflora with increasing local inflammation.

Discriminant Subspace Low-Rank Representation Algorithm for Electroencephalography-Based Alzheimers Disease Recognition.

Alzheimers disease (AD) is a chronic progressive neurodegenerative disease that often occurs in the elderly. Electroencephalography (EEG) signals have a strong correlation with neuropsychological test results and brain structural changes. It has become an effective aid in the early diagnosis of AD by exploiting abnormal brain activity. Because the original EEG has the characteristics of weak amplitude, strong background noise and randomness, the research on intelligent AD recognition based on machine learning is still in the exploratory stage. This paper proposes the discriminant subspace low-rank representation (DSLRR) algorithm for EEG-based AD and mild cognitive impairment (MCI) recognition. The subspace learning and low-rank representation are flexibly integrated into a feature representation model. On the one hand, based on the low-rank representation, the graph discriminant embedding is introduced to constrain the representation coefficients, so that the robust representation coefficients can preserve the local manifold structure of the EEG data. On the other hand, the least squares regression, principle component analysis, and global graph embedding are introduced into the subspace learning, to make the model more discriminative. The objective function of DSLRR is solved by the inexact augmented Lagrange multiplier method. The experimental results show that the DSLRR algorithm has good classification performance, which is helpful for in-depth research on AD and MCI recognition.

Obesity is recognized as a significant risk factor for Alzheimers disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fathigh sugar diet (HFD). We focused on three mouse models created through the IUJAXPITT MODEL-AD Center. These included a combined risk model with

The Future of Seed Amplification Assays and Clinical Trials.

Prion-like seeded misfolding of host proteins is the leading hypothesised cause of neurodegenerative diseases. The exploitation of the mechanism in the protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays have transformed prion disease research and diagnosis and have steadily become more widely used for research into other neurodegenerative disorders. Clinical trials in adult neurodegenerative diseases have been expensive, slow, and disappointing in terms of clinical benefits. There are various possible factors contributing to the failure to identify disease-modifying treatments for adult neurodegenerative diseases, some of which include limited accuracy of antemortem clinical diagnosis resulting in the inclusion of patients with the incorrect pathology for the therapeutic the role of co-pathologies in neurodegeneration rendering treatments targeting one pathology alone ineffective treatment of the primary neurodegenerative process too late, after irreversible secondary processes of neurodegeneration have become established or neuronal loss is already extensive and preclinical models used to develop treatments not accurately representing human disease. The use of seed amplification assays in clinical trials offers an opportunity to tackle these problems by sensitively detecting

Functional Connectivity Dynamics Altered of the Resting Brain in Subjective Cognitive Decline.

Subjective cognitive decline (SCD) appears in the preclinical stage of the Alzheimers disease continuum. In this stage, dynamic features are more sensitive than static features to reflect early subtle changes in functional brain connectivity. Therefore, we studied local and extended dynamic connectivity of the resting brain of people with SCD to determine their intrinsic brain changes. We enrolled cognitively normal older adults from the communities and divided them into SCD and normal control (NC) groups. We used mean dynamic amplitude of low-frequency fluctuation (mdALFF) to evaluate region of interest (ROI)-wise local dynamic connectivity of resting-state functional MRI. The dynamic functional connectivity (dFC) between ROIs was tested by whole-brain-based statistics. When comparing SCD ( The local dynamic connectivity of SCD decreased in brain regions of cognitive executive control. Meanwhile, compensatory visual efforts and bottom-up attention rose. Mixed decrease and compensatory increase of dynamics of intrinsic brain activity suggest the transitional nature of SCD. The FPN local dynamics balance subjective and objective cognition and maintain cognitive preservation in preclinical dementia. Aberrant triple network model features the dFC alternations of SCD. Finally, the right lateralization phenomenon emerged early in the dementia continuum and affected local dynamic connectivity.

Epigenetics in Alzheimers Disease.

Alzheimers disease (AD) is a neurodegenerative disease with unknown pathogenesis and complex pathological manifestations. At present, a large number of studies on targeted drugs for the typical pathological phenomenon of AD (Aβ) have ended in failure. Although there are some drugs on the market that indirectly act on AD, their efficacy is very low and the side effects are substantial, so there is an urgent need to develop a new strategy for the treatment of AD. An increasing number of studies have confirmed epigenetic changes in AD. Although it is not clear whether these epigenetic changes are the cause or result of AD, they provide a new avenue of treatment for medical researchers worldwide. This article summarizes various epigenetic changes in AD, including DNA methylation, histone modification and miRNA, and concludes that epigenetics has great potential as a new target for the treatment of AD.

The Influence of 24-h Ambulatory Blood Pressure on Cognitive Function and Neuropathological Biomarker in Patients With Alzheimers Disease.

This study aimed to investigate the influence of 24-h ambulatory blood pressure (BP) on cognitive function and neuropathological biomarkers in patients with Alzheimers disease (AD) at the stages of mild cognitive impairment (MCI) and dementia. The patients with AD were divided into the MCI (AD-MCI) group and the dementia (AD-D) group. Notably, 24-h BP variables, including BP level, coefficient of variation (CV) of BP, and pulse pressure, were collected and compared between the two groups. The correlations between 24-h BP variables and the scores of cognitive domains were analyzed. The independent influencing factors of cognitive domains of patients with AD were investigated. The levels of neuropathological biomarkers of AD, including β amyloid (Aβ) Daytime CV of systolic BP (SBP) was significantly increased in the AD-D group compared to that in the AD-MCI group. The 24-h and daytime CV of SBP and ambulatory pulse pressure were significantly and negatively correlated with memory score. The average 24-h and average daytime SBP level and CV of SBP, daytime CV of diastolic BP (DBP), and 24-h, daytime, and night-time ambulatory pulse pressure were significantly and negatively correlated with language score. The average 24-h SBP level, daytime CV of SBP, and 24-h, daytime, and night-time ambulatory pulse pressure were significantly and negatively correlated with attention score. Further analysis indicated that daytime CV of SBP as well as age and course of disease were the independent influencing factors of language. Age was also the independent influencing factor of memory and attention of patients with AD. T-tau level in CSF in the AD-D group was significantly higher than that in the AD-MCI group, but the levels of Aβ Daytime CV of SBP was the independent influencing factor of language in patients with AD. The AD-D patients had significantly severe neurodegeneration than AD-MCI patients, which was, however, not through the influence of 24-h ambulatory BP variables on neuropathological biomarkers of AD.

Posterior cingulate cortex reveals an expression profile of resilience in cognitively intact elders.

The posterior cingulate cortex, a key hub of the default mode network, underlies autobiographical memory retrieval and displays hypometabolic changes early in Alzheimer disease. To obtain an unbiased understanding of the molecular pathobiology of the aged posterior cingulate cortex, we performed RNA sequencing (RNA-seq) on tissue obtained from 26 participants of the Rush Religious Orders Study (11 males15 females aged 76-96 years) with a pre-mortem clinical diagnosis of no cognitive impairment and post-mortem neurofibrillary tangle Braak Stages III, III, and IV. Transcriptomic data were gathered using next-generation sequencing of RNA extracted from posterior cingulate cortex generating an average of 60 million paired reads per subject. Normalized expression of RNA-seq data was calculated using a global gene annotation and a microRNA profile. Differential expression (DESeq2, edgeR) using Braak staging as the comparison structure isolated genes for dimensional scaling, associative network building and functional clustering. Curated genes were correlated with the Mini-Mental State Examination and semantic, working and episodic memory, visuospatial ability, and a composite Global Cognitive Score. Regulatory mechanisms were determined by co-expression networks with microRNAs and an overlap of transcription factor binding sites. Analysis revealed 750 genes and 12 microRNAs significantly differentially expressed between Braak Stages III and IIIIV and an associated six groups of transcription factor binding sites. Inputting significantly different genenetwork data into a functional annotation clustering model revealed elevated presynaptic, postsynaptic and ATP-related expression in Braak Stages III and IV compared with Stages III, suggesting these pathways are integral for cognitive resilience seen in unimpaired elderly subjects. Principal component analysis and Kruskal-Wallis testing did not associate Braak stage with cognitive function. However, Spearman correlations between genes and cognitive test scores followed by network analysis revealed upregulation of classes of synaptic genes positively associated with performance on the visuospatial perceptual orientation domain. Upregulation of key synaptic genes suggests a role for these transcripts and associated synaptic pathways in cognitive resilience seen in elders despite Alzheimer disease pathology and dementia.

Signatures of somatosensory cortical dysfunction in Alzheimers disease and HIV-associated neurocognitive disorder.

Alzheimers disease is the most common type of dementia in the general population, while HIV-associated neurocognitive disorder is the most common neurological comorbidity in those infected with HIV and affects between 40 and 70% of this population. Both conditions are associated with cognitive impairment and have been associated with aberrant functioning in sensory cortices, but far less is known about their disparate effects on neural activity. Identifying such disparate effects is important because it may provide critical data on the similarities and differences in the neuropathology underlying cognitive decline in each condition. In the current study, we utilized magnetoencephalography, extensive neuropsychological testing and a paired-pulse somatosensory gating paradigm to probe differences in somatosensory processing in participants from two ongoing magnetoencephalography studies. The resulting participant groups included 27 cognitively normal controls, 26 participants with HIV-associated neurocognitive disorder and 21 amyloid biomarker-confirmed patients with Alzheimers disease. The data were imaged using a beamformer and voxel time series were extracted to identify the oscillatory dynamics serving somatosensory processing, as well as the amplitude of spontaneous cortical activity preceding stimulation onset. Our findings indicated that people with Alzheimers disease and HIV-associated neurocognitive disorder exhibit normal somatosensory gating but have distinct aberrations in other elements of somatosensory cortical function. Essentially, those with Alzheimers disease exhibited accentuated neural responses to somatosensory stimulation, along with spontaneous gamma activity preceding stimulus onset. In contrast, those with HIV-associated neurocognitive disorder exhibited normal responses to somatosensory stimulation but had sharply elevated spontaneous gamma activity prior to stimulus onset. These distinct aberrations may reflect the impact of different neuropathological mechanisms underlying each condition. Further, given the differential pattern of deficits in somatosensory cortical function, these measures may function as unique biomarkers in each condition and be useful in identifying persons with HIV who may go on to develop Alzheimers disease.

Inbred Mice Again at Stake How the Cognitive Profile of the Wild-Type Mouse Background Discloses Pathogenic Effects of APP Mutations.

Increasing efforts have been made in the last decades to increase the face validity of Alzheimers disease (AD) mouse models. Main advancements have consisted in generating AD mutations closer to those identified in humans, enhancing genetic diversity of wild-type backgrounds, and choosing protocols much apt to reveal AD-like cognitive dysfunctions. Nevertheless, two aspects remain less considered the cognitive specialization of inbred strains used as recipient backgrounds of mutations and the heuristic importance of studying destabilization of memory circuits in pre-symptomatic mice facing cognitive challenges. This article underscores the relevance of these behavioralexperimental aspects by reviewing data which show that (i) inbred mice differ in their innate predisposition to rely on episodic vs. procedural memory, which implicates differential sensitivity to mutations aimed at disrupting temporal lobe-dependent memory, and that (ii) investigating training-driven neural alterations in asymptomatic mutants unveils early synaptic damage, which considerably anticipates detection of AD first signs.

The Protective Effects of Zeaxanthin on Amyloid-β Peptide 1-42-Induced Impairment of Learning and Memory Ability in Rats.

Zeaxanthin (ZEA) as one of the biologically active phytochemicals presents a neuroprotective effect. Since ZEA may play its anti-oxidative role in neurodegenerative diseases including Alzheimers disease (AD), we hypothesized cognitive defects could be prevented or deferred by ZEA pre-treatment. All the rats were randomly divided into four groups (control, Aβ1-42, ZEA, and ZEA Aβ groups). Learning and memory ability of rats, cerebrovascular ultrastructure changes, the redox state, endothelin-1 (ET-1) level, and amyloid-β peptide (Aβ) level in plasma and the Aβ transport receptors which are advanced glycation end products (RAGEs) and LDL receptor-related protein-1 (LRP-1) and interleukin-1β (IL-1β) expressions in the cerebrovascular tissue were measured in the present study. The escape latency and frequency of spanning the position of platform showed significant differences between the Aβ group and ZEA treatment groups. ZEA could prevent the ultrastructure changes of cerebrovascular tissue. In addition, ZEA also showed the protective effects on regulating redox state, restraining ET-1 levels, and maintaining Aβ homeostasis in plasma and cerebrovascular. Moreover, the disordered expressions of RAGE and LRP-1 and IL-1β induced by Aβ1-42 could be prevented by the pre-treatment of ZEA. ZEA pre-treatment could prevent learning and memory impairment of rats induced by Aβ1-42. This neuroprotective effect might be attributable to the anti-oxidative and anti-inflammatory effects of ZEA on maintaining the redox state and reducing the Aβ level through regulating the Aβ transport receptors and inflammatory cytokine of the cerebrovascular tissue.

Will Sirtuin 2 Be a Promising Target for Neuroinflammatory Disorders

Neuroinflammatory disorder is a general term that is associated with the progressive loss of neuronal structure or function. At present, the widely studied diseases with neuroinflammatory components are mainly divided into neurodegenerative and neuropsychiatric diseases, namely, Alzheimers disease, Parkinsons disease, depression, stroke, and so on. An appropriate neuroinflammatory response can promote brain homeostasis, while excessive neuroinflammation can inhibit neuronal regeneration and damage the central nervous system. Apart from the symptomatic treatment with cholinesterase inhibitors, antidepressantsanxiolytics, and neuroprotective drugs, the treatment of neuroinflammation is a promising therapeutic method. Sirtuins are a host of class III histone deacetylases, that require nicotinamide adenine dinucleotide for their lysine residue deacetylase activity. The role of sirtuin 2 (SIRT2), one of the sirtuins, in modulating senescence, myelin formation, autophagy, and inflammation has been widely studied. SIRT2 is associated with many neuroinflammatory disorders considering it has deacetylation properties, that regulate the entire immune homeostasis. The aim of this review was to summarize the latest progress in regulating the effects of SIRT2 on immune homeostasis in neuroinflammatory disorders. The overall structure and catalytic properties of SIRT2, the selective inhibitors of SIRT2, the relationship between immune homeostasis and SIRT2, and the multitasking role of SIRT2 in several diseases with neuroinflammatory components were discussed.

The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration.

Damage to DNA is generally considered to be a harmful process associated with aging and aging-related disorders such as neurodegenerative diseases that involve the selective death of specific groups of neurons. However, recent studies have provided evidence that DNA damage and its subsequent repair are important processes in the physiology and normal function of neurons. Neurons are unique cells that form new neural connections throughout life by growth and re-organisation in response to various stimuli. This plasticity is essential for cognitive processes such as learning and memory as well as brain development, sensorial training, and recovery from brain lesions. Interestingly, recent evidence has suggested that the formation of double strand breaks (DSBs) in DNA, the most toxic form of damage, is a physiological process that modifies gene expression during normal brain activity. Together with subsequent DNA repair, this is thought to underlie neural plasticity and thus control neuronal function. Interestingly, neurodegenerative diseases such as Alzheimers disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntingtons disease, manifest by a decline in cognitive functions, which are governed by plasticity. This suggests that DNA damage and DNA repair processes that normally function in neural plasticity may contribute to neurodegeneration. In this review, we summarize current understanding about the relationship between DNA damage and neural plasticity in physiological conditions, as well as in the pathophysiology of neurodegenerative diseases.

Transcriptomic Profile of Blood-Brain Barrier Remodeling in Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by amyloid β (Aβ) peptide deposition within the walls of medium to small-caliber blood vessels, cerebral microhemorrhage, and blood-brain barrier (BBB) leakage. It is commonly associated with late-stage Alzheimers disease. BBB dysfunction is indicated as a pathological substrate for CAA progression with hyperpermeability, enhancing the extravasation of plasma components and inducing neuroinflammation, further worsening BBB injury and contributing to cognitive decline. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alterations with vascular dementia and Alzheimers disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The present study aimed to elucidate the transcriptional profile of the cerebral microvessels (BBB) in a murine model with CAA vasculopathy to define potential causes and underlying mechanisms of BBB injury. A comprehensive RNA sequencing analysis was performed of CAA vasculopathy in Tg-SwDI mice at 6 and 18 months in comparison to age-matched wildtype controls to examine how age and amyloid accumulation impact the transcriptional signature of the BBB. Results indicate that Aβ has a critical role in triggering brain endothelial cell and BBB dysfunction in CAA vasculopathy, causing an intense proinflammatory response, impairing oxidative metabolism, altering the coagulation status of brain endothelial cells, and remodeling barrier properties. The proinflammatory response includes both adaptive and innate immunity, with pronounced induction of genes that regulate macrophagemicroglial activation and chemokinesadhesion molecules that support T and B cell transmigration. Age has an important impact on the effects of Aβ, increasing the BBB injury in CAA vasculopathy. However, early inflammation, particularly microgliamacrophage activation and the mediators of B lymphocytes activities are underlying processes of BBB hyperpermeability and cerebral microbleeds in the early stage of CAA vasculopathy. These findings reveal a specific profile of the CAA-associated BBB injury that leads to a full progression of CAA.

NAV3 Is a Novel Prognostic Biomarker Affecting the Immune Status of the Tumor Microenvironment in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Tumor microenvironment (TME) plays a crucial role in the development of CRC. With the deep understanding of TME function, growing studies have demonstrated that alteration in tumor-infiltrating immune cells (TICs) and gene expressions are associated with clinical outcomes of various tumors. In this study, we aimed to recognize critical prognostic genes involved in immune states in TME of CRC. Hence, the proportion of TICs and the number of immune and stromal components in CRC samples from TCGA datasets were calculated by the use of CIBERSORT and ESTIMATE calculation methods. Different assays were applied to collect differential expression genes (DEGs) shared by the ImmuneScore and StromalScore. DEGs were further analyzed by the use of univariate Cox regression. Our attention focused on neuron navigator 3 (NAV3) which was highly expressed in CRC specimens and associated with an advanced clinical stage and poor prognosis of CRC patients. KEGG assays revealed that NAV3 may be involved in Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, FoxO signaling pathway, and human papillomavirus infection. Correlation assays showed that macrophage M0 and B cells memory, NK cells activated, dendritic cells resting, T cells CD4 memory activated, and T cells CD8 were correlated with NAV3 expression, indicating that NAV3 may represent the immune status of TME. Finally, RT-PCR confirmed that NAV3 expression was distinctly increased in CRC cells, and its knockdown suppressed the proliferation of CRC cells. Overall, NAV3 could be used as a novel predictor for TME of CRC and might be a novel prognostic biomarker. In the future, drugs targeting NAV3 might be developed as a potential immunotherapy for CRC patients.

Astrocytes in Neurodegeneration Inspiration From Genetics.

Despite the discovery of numerous molecules and pathologies, the pathophysiology of various neurodegenerative diseases remains unknown. Genetics participates in the pathogenesis of neurodegeneration. Neural dysfunction, which is thought to be a cell-autonomous mechanism, is insufficient to explain the development of neurodegenerative disease, implying that other cells surrounding or related to neurons, such as glial cells, are involved in the pathogenesis. As the primary component of glial cells, astrocytes play a variety of roles in the maintenance of physiological functions in neurons and other glial cells. The pathophysiology of neurodegeneration is also influenced by reactive astrogliosis in response to central nervous system (CNS) injuries. Furthermore, those risk-gene variants identified in neurodegenerations are involved in astrocyte activation and senescence. In this review, we summarized the relationships between gene variants and astrocytes in four neurodegenerative diseases, including Alzheimers disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinsons disease (PD), and provided insights into the implications of astrocytes in the neurodegenerations.

Downregulation of Neurofilament Light Chain Expression in Human Neuronal-Glial Cell Co-Cultures by a Microbiome-Derived Lipopolysaccharide-Induced miRNA-30b-5p.

Microbiome-derived Gram-negative bacterial lipopolysaccharide (LPS) has been shown by multiple laboratories to reside within Alzheimers disease (AD)-affected neocortical and hippocampal neurons. LPS and other pro-inflammatory stressors strongly induce a defined set of NF-kB (p50p65)-sensitive human microRNAs, including a brain-enriched

Frequency of Neurological Diseases After COVID-19, Influenza AB and Bacterial Pneumonia.

COVID-19 might affect the incidence of specific neurological diseases, but it is unknown if this differs from the risk following other infections. Here, we characterized the frequency of neurodegenerative, cerebrovascular, and immune-mediated neurological diseases after COVID-19 compared to individuals without COVID-19 and those with other respiratory tract infections. This population-based cohort study utilized electronic health records covering 50% of Denmarks population ( In total, 919,731 individuals were tested for COVID-19, of whom 43,375 tested positive (35,362 outpatients, 8,013 inpatients). Compared to COVID-negative outpatients, COVID-19 positive outpatients had an increased RR of Alzheimers disease (RR 3.5 95%CI 2.2-5.5) and Parkinsons disease (RR 2.6 95%CI 1.7-4.0), ischemic stroke (RR 2.7 95%CI 2.3-3.2) and intracerebral hemorrhage (RR 4.8 95%CI 1.8-12.9). However, when comparing to other respiratory tract infections, only the RR for ischemic stroke was increased among inpatients with COVID-19 when comparing to inpatients with influenza (RR 1.7 95%CI 1.2-2.4) and only for those >80 years of age when comparing to inpatients with bacterial pneumonia (RR 2.7 95%CI 1.2-6.2). Frequencies of multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome and narcolepsy did not differ after COVID-19, influenza and bacterial pneumonia. The risk of neurodegenerative and cerebrovascular, but not neuroimmune, disorders was increased among COVID-19 positive outpatients compared to COVID-negative outpatients. However, except for ischemic stroke, most neurological disorders were not more frequent after COVID-19 than after other respiratory infections.

Mild Traumatic Brain Injury Results in Significant and Lasting Cortical Demyelination.

Despite contributing to neurocognitive deficits, intracortical demyelination after traumatic brain injury (TBI) is understudied. This study uses magnetic resonance imaging (MRI) to map intracortical myelin and its change in healthy controls and after mild TBI (mTBI). Acute mTBI involves reductions in relative myelin content primarily in lateral occipital regions. Demyelination mapped 6 months post-injury is significantly more severe than that observed in typical aging (

Neuropsychiatric or Behavioral and Psychological Symptoms of Dementia (BPSD) Focus on Prevalence and Natural History in Alzheimers Disease and Frontotemporal Dementia.

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimers disease (AD) in three stages (i) pre-T0 (before the onset of the disease) (ii) T0 or manifested disease (from the onset to 5 years) (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritabilityaffective lability, and agitationaggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important red flag in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

Association of Dietary Vitamin K Intake With Cognition in the Elderly.

Several previous studies discussed the association between vitamin K (VK) status and cognition. But the association between dietary VK consumption and cognitive performance in the elderly was not well understood. Therefore, we investigated the correlation between dietary VK intake and the cognition of the elderly. Our research used the data of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The dietary intake of VK was assessed by two 24-h dietary recalls. The cognitive function was measured in the survey of NHANES, including the Consortium to Establish a Registry for Alzheimers disease Word Learning subtest (CERAD W-L), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Logistic regression and restricted cubic spline models were applied to assess the relationship between dietary VK intake and cognition. Compared with the lowest dietary VK intake group, the multivariate-adjusted odds ratio (OR) 95% confidence interval (95% CI) of low CERAD W-L score for the highest intake group was 0.39 (0.26-0.60), the multivariate-adjusted OR (95% CI) of low AFT score was 0.59 (0.38-0.92), and the multivariate-adjusted OR (95% CI) of low DSST score was 0.44 (0.29-0.65), respectively. There was an L-shaped dose-response relationship between dietary VK intake and low CERAD W-L score. There was a linear dose-response relationship between dietary VK intake and low AFT score, and there was also a linear dose-response relationship for the low DSST score. In addition, we also found a negative association between VK from vegetables and the risk of low CERAD W-L scores. Dietary VK intake and VK intake from vegetables were inversely related to the risk of low cognitive performance of the elderly.

Effect of icaritin on autophagy-related protein expression in TDP-43-transfected SH-SY5Y cells.

To study the protective effect and mechanism of icaritin (ICT) in a SH-SY5Y cells with virus-loaded TAR DNA-binding domain protein 43(TDP-43) by examining the effect of ICT on the expression of autophagy-related proteins in TDP-43-infected SH-SY5Y cells. A TDP-43-induced neuronal cell injury model was established by transfecting well-growing SH-SY5Y cells with virus loaded with the TDP-43 gene. The changes in cell viability were detected by the CCK-8 method. After successful transfection, the establishment of the model was verified by real-time quantitative PCR (qPCR) and Western blot methods. After the cells were subjected to drug intervention with ICT, the changes in the expression levels of TDP-43, cleaved Caspase-3, LC3 III, Beclin-1 and p62 were detected by Western blotting. After ICT intervention, it was found that compared with that of the TDP-43 group, the cell viability of the TDP-43ICT group increased, the expression level of TDP-43 decreased, and the expression levels of the apoptotic protein cleaved Caspase-3, autophagy protein Beclin-1, and LC3-III decreased, while the expression level of the autophagy protein p62 increased. ICT has a protective effect on the SH-SY5Y cell injury model transfected with TDP-43. This protective effect may be related to reducing the protein expression of TDP-43 and inhibiting autophagy.