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Circadian disruption and sleep disorders in neurodegeneration.

Disruptions of circadian rhythms and sleep cycles are common among neurodegenerative diseases and can occur at multiple levels. Accumulating evidence reveals a bidirectional relationship between disruptions of circadian rhythms and sleep cycles and neurodegenerative diseases. Circadian disruption and sleep disorders aggravate neurodegeneration and neurodegenerative diseases can in turn disrupt circadian rhythms and sleep. Importantly, circadian disruption and various sleep disorders can increase the risk of neurodegenerative diseases. Thus, harnessing the circadian biology findings from preclinical and translational research in neurodegenerative diseases is of importance for reducing risk of neurodegeneration and improving symptoms and quality of life of individuals with neurodegenerative disorders via approaches that normalize circadian in the context of precision medicine. In this review, we discuss the implications of circadian disruption and sleep disorders in neurodegenerative diseases by summarizing evidence from both human and animal studies, focusing on the bidirectional links of sleep and circadian rhythms with prevalent forms of neurodegeneration. These findings provide valuable insights into the pathogenesis of neurodegenerative diseases and suggest a promising role of circadian-based interventions.

A novel isolation method for spontaneously released extracellular vesicles from brain tissue and its implications for stress-driven brain pathology.

Extracellular vesicles (EVs), including small EVs (sEVs) such as exosomes, exhibit great potential for the diagnosis and treatment of brain disorders, representing a valuable tool for precision medicine. The latter demands high-quality human biospecimens, especially in complex disorders in which pathological and specimen heterogeneity, as well as diverse individual clinical profile, often complicate the development of precision therapeutic schemes and patient-tailored treatments. Thus, the collection and characterization of physiologically relevant sEVs are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV fractions with intracellular vesicles. Based on multiscale analytical platforms such as cryo-EM, label-free proteomics, advanced flow cytometry, and ExoView analyses, we compared and characterized the EV fraction isolated with this novel method with a classical digestion-based EV isolation procedure. Moreover, EV biogenesis was pharmacologically manipulated with either GW4869 or picrotoxin to assess the validity of the spontaneous-release method, while the injection of labelled-EVs into the mouse brain further supported the integrity of the isolated vesicles. We hereby present an efficient purification method that captures a sEV-enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesissecretion of sEVs was pharmacologically manipulated, as well as under animals exposure to chronic stress, a clinically relevant precipitant of brain pathologies, such as depression and Alzheimers disease. Our findings show that the released method monitors the drug-evoked inhibition or enhancement of sEVs secretion while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress-driven brain pathology. Overall, the spontaneous release method of sEV yield may contribute to the characterization and biomarker profile of physiologically relevant brain-derived sEVs in brain function and pathology. Video Abstract.

Implementing a home-based personalised cognitive rehabilitation intervention for people with mild-to-moderate dementia GREAT into Practice.

Evidence-based rehabilitative interventions, if widely implemented, could equip people with dementia and their families to manage life with the condition and reduce the need for health and care services. The aim of this translational study, building on evidence from the GREAT randomised controlled trial, was to develop a foundation for implementing the GREAT Cognitive Rehabilitation intervention in community-based services for people with mild-to-moderate dementia. Key elements of the implementation strategy were identifying and supporting managerial and clinical leadership, conducting collaborative planning and target-setting, training and supporting practitioners, and providing external facilitation. We developed implementation plans with, and trained staff in, 14 organisations. We subsequently worked closely with 11 of these, 10 National Health Service organisations and one private home care provider, to support practitioners to deliver GREAT Cognitive Rehabilitation over a 12-month period. Outcome evaluation examined the perspectives of local steering group members, practitioners and service users, and the reach, effectiveness and cost of the intervention. Implementation was disrupted by the COVID-19 pandemic, but six organisations completed at least six months of intervention delivery. Forty-one practitioners, mainly occupational therapists, provided the intervention, and 54 people with dementia completed a course of GREAT Cognitive Rehabilitation. Goal attainment by people with dementia exceeded levels of improvement seen in the original trial. People with dementia, carers, practitioners and steering group members all evaluated the intervention positively, and economic analysis indicated that the intervention could be provided at modest cost. However, we identified a range of mainly organisational barriers that impeded implementation and limited the potential for sustainability. GREAT Cognitive Rehabilitation benefits people with dementia, can be delivered effectively at modest cost in routine services, and is viewed positively by people with dementia, family carers and practitioners. To fully realise these benefits and achieve widespread and sustainable implementation, however, requires sufficient resources and a reorientation of service priorities towards preventive and rehabilitative approaches. National Institute for Health Research (NIHR) Central Portfolio Management System, registration number 38994.

Resistance training restores skeletal muscle atrophy and satellite cell content in an animal model of Alzheimers disease.

Alzheimers disease (AD) is the most common neurodegenerative disease, and numerous recent findings suggest that several pathologic signs, including loss of muscle strength and mass, are also detected in these patients. In the present study, we evaluated muscle cross-sectional area (CSA), myonuclear number, satellite cell (SC) content, and myosin heavy chain (MyHC) types in an animal model of AD and examined the possible role of resistance training in controlling skeletal muscle size in this disease. Fifty-eight male rats were randomly divided into four groups healthy-control (H-C), healthy-exercise (H-Ex), Alzheimer-control (A-C), and Alzheimer-exercise (A-Ex). AD was induced by the single injection of 1-42 amyloid into the CA1 region of the hippocampus (1 μlsite). The rats in H-Ex and A-Ex groups performed a 5-week resistance training period (17 sessions). The results indicated that AD induces significant skeletal muscle atrophy and reduces the myonuclear number and SC content in gastrocnemius muscle in both whole muscle cross-sections and isolated myofibers. Interestingly, we did not find any significant differences in the different MyHC distributions of AD animals compared with controls, while resistance training significantly increased the CSA of MyHC IIb fibers in both AD and healthy animals. Altogether, these observations suggest that the skeletal muscle of AD animals are more prone to atrophy and loss of myonuclear number and satellite cell content, while resistance training successfully restores these impairments.

Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.

Alzheimers disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (Aβ) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male App

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations.

Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising progranulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant allele, as well as approaches to directly increase progranulin levels by delivery across the blood-brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be the next frontier in the treatment of neurodegenerative disease.

Anti-inflammatory Action of BT75, a Novel RARα Agonist, in Cultured Microglia and in an Experimental Mouse Model of Alzheimers Disease.

BT75, a boron-containing retinoid, is a novel retinoic acid receptor (RAR)α agonist synthesized by our group. Previous studies indicated that activation of retinoic acid (RA) signaling may attenuate progression of Alzheimers disease (AD). Presently, we aimed to examine the anti-inflammatory effect of BT75 and explore the possible mechanism using cultured cells and an AD mouse model. Pretreatment with BT75 (1-25 µM) suppressed the release of nitric oxide (NO) and IL-1β in the culture medium of mouse microglial SIM-A9 cells activated by LPS. BMS195614, an RARα antagonist, partially blocked the inhibition of NO production by BT75. Moreover, BT75 attenuated phospho-Akt and phospho-NF-κB p65 expression augmented by LPS. In addition, BT75 elevated arginase 1, IL-10, and CD206, and inhibited inducible nitric oxide synthase (iNOS) and IL-6 formation in LPS-treated SIM-A9 cells, suggesting the promotion of M1-M2 microglial phenotypic polarization. C57BL6 mice were injected intracerebroventricularly (icv) with streptozotocin (STZ) (3 mgkg) to provide an AD-like mouse model. BT75 (5 mgkg) or the vehicle was intraperitoneally (ip) injected to icv-STZ mice once a day for 3 weeks. Immunohistochemical analyses indicated that GFAP-positive cells and rod or amoeboid-like Iba1-positive cells, which increased in the hippocampal fimbria of icv-STZ mice, were reduced by BT75 treatment. Western blot results showed that BT75 decreased levels of neuronal nitric oxide synthase (nNOS), GFAP, and phosphorylated Tau, and increased levels of synaptophysin in the hippocampus of icv-STZ mice. BT75 may attenuate neuroinflammation by affecting the AktNF-κB pathway and microglial M1-M2 polarization in LPS-stimulated SIM-A9 cells. BT75 also reduced AD-like pathology including glial activation in the icv-STZ mice. Thus, BT75 may be a promising anti-inflammatory and neuroprotective agent worthy of further AD studies.

Accurate Detection of α-Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinsons Disease in the DeNovo Parkinson (DeNoPa) Cohort.

Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinsons disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD). The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline. We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter-single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society-Unified Parkinsons Disease Rating Scale, and various cognitive and nonmotor scales. αS-SAA detected αSyn-seeds in baseline PD-CSF with 98% accuracy. αSyn-seeds were detected in 93% of the iRBD cases. αS-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-αSyn aggregation disorder. For synucleinopathies, αS-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression. Our results confirm αS-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. αS-SAA conditions reported here are highly sensitive, enabling the detection of αSyn-seeds in CSF from iRBD just months after the first symptoms, suggesting that αSyn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, αSyn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion. © 2023 International Parkinson and Movement Disorder Society.

Greater subjective cognitive decline severity is associated with worse memory performance and lower entorhinal cerebral blood flow in healthy older adults.

Subjective cognitive decline (SCD) is a potential early risk marker for Alzheimers disease (AD), but its utility may vary across individuals. We investigated the relationship of SCD severity with memory function and cerebral blood flow (CBF) in areas of the middle temporal lobe (MTL) in a cognitively normal and overall healthy sample of older adults. Exploratory analyses examined if the association of SCD severity with memory and MTL CBF was different in those with lower and higher cardiovascular disease (CVD) risk status. Fifty-two community-dwelling older adults underwent magnetic resonance imaging, neuropsychological testing, and were administered the Everyday Cognition Scale (ECog) to measure SCD. Regression models investigated whether ECog scores were associated with memory performance and MTL CBF, followed by similar exploratory regressions stratified by CVD risk status (i.e., lower vs higher stroke risk). Higher ECog scores were associated with lower objective memory performance and lower entorhinal cortex CBF after adjusting for demographics and mood. In exploratory stratified analyses, these associations remained significant in the higher stroke risk group only. Our preliminary findings suggest that SCD severity is associated with cognition and brain markers of preclinical AD in otherwise healthy older adults with overall low CVD burden and that this relationship may be stronger for individuals with higher stroke risk, although larger studies with more diverse samples are needed to confirm these findings. Our results shed light on individual characteristics that may increase the utility of SCD as an early risk marker of cognitive decline.

Cornuside, by regulating the AGEs-RAGE-IκBα-ERK12 signaling pathway, ameliorates cognitive impairment associated with brain aging.

Anti-Alzheimers disease (AD) drugs can only change the symptoms of cognitive impairment in a short time but cannot prevent or completely cure AD. Thus, a more effective drug is urgently needed. Cornuside is extracted from Corni Fructus, a traditional Chinese medicine that plays an important role in treating dementia and other age-related diseases. Thus, the study aimed to explore the effects and mechanisms of Cornuside on the D-galactose (D-Gal) induced aging mice accompanied by cognitive decline. Initially, we found that Cornuside improved the learning and memory abilities of D-Gal-treated mice in behavioral experiments. Pharmacological experiments indicated that Cornuside acted on anti-oxidant and anti-inflammatory effects. Cornuside also reversed acetylcholin esterase (AChE) activity. Meanwhile, pathology tests showed that Cornuside had a protective effect on neuron damage. Cornuside increased the expression of brain-derived neurotrophic factor (BDNF), and down-regulated the expression of receptor for advanced glycosylation end products (RAGE), ionized calcium binding adapter molecule 1 (Iba1), and glial fibrillary acidic protein (GFAP) respectively. Further studies claimed that Cornuside had important effects on the expression of IκBα and extracellular signal-regulated kinases 12 (ERK12). These effects might be achieved through regulating the AGEs-RAGE-IκBα-ERK12 signaling pathway, among which, ERK12 might be the key protein. The study provides direct preclinical evidence for the research of Cornuside, which may become an excellent candidate drug for the treatment of aging-related AD.

Eicosapentaenoic Acid Protects against Metabolic Impairments in the APPswePS1dE9 Alzheimers Disease Mouse Model.

Alzheimers disease (AD) is an age-related neurodegenerative disease characterized by amyloid-β (Aβ) plaques. Systemic inflammation and obesity may exacerbate AD pathogenesis. We previously reported anti-inflammatory and anti-obesity effects of EPA in mice. We aimed to determine whether EPA reduces obesity-associated metabolic dysfunctions and Aβ accumulation in AD amyloidogenic mice. Two-mo-old APPswePS1dE9 transgenic (TG) mice and non-TG littermates were randomly assigned to low fat (LF 10% kcal fat), high fat (HF 45% kcal fat), or EPA (36 gkg)-supplemented HF diets. Body composition, glucose tolerance, and EE were measured, and serum and brain metabolic markers were tested 32 wk postintervention. Outcomes were statistically analyzed via 3-factor ANOVA, modeling genotype, sex, and diet interactions. HF-fed males gained more weight than females (Δ 61 mg P < 0.001). Compared with LF, HF increased body weights of wild-type (WT) males (Δ 31 mg P < 0.001). EPA reduced HF-induced weight gain in WT males (Δ 24 mg P 0.054) but not in females. HF mice showed decreased glucose clearance and respiratory energy compared with LF-fed groups (Δ -1.31 gdL P < 0.001), with no significant effects of EPA. However, EPA conferred metabolic improvements by decreasing serum leptin and insulin (Δ -2.51 gmL and Δ -0.694 ngmL, respectively compared with HF, P ≤ 0.05) and increasing adiponectin (Δ 21.6 ngmL P < 0.001). As we expected, TG mice expressed higher serum and brain Aβ than WT mice (Δ 0.131 ngmL P < 0.001 and Δ 0.56% P < 0.01, respectively), and EPA reduced serum Aβ To our knowledge, this is the first report that EPA reduces serum Aβ

A systematic review on botany, ethnopharmacology, quality control, phytochemistry, pharmacology and toxicity of Arctium lappa L. fruit.

Arctium lappa L., is a biennial plant that grows around the Eurasia. Many parts of Arctium lappa L. (roots, leaves and fruits, etc.) are medically used in different countries. Arctium lappa L. fruit, also called Arctii Fructus, is traditionally applied to dispel wind-heat, ventilate lung to promote eruption, remove toxicity substance and relieve sore throat. The review aims to integrate the botany, ethnopharmacology, quality control, phytochemistry, pharmacology, derivatives and toxicity information of Arctii Fructus, so as to facilitate future research and explore the potential of Arctii Fructus as an agent for treating diseases. Related knowledge about Arctii Fructus were acquired from Science Direct, GeenMedical, PubMed, China National Knowledge Infrastructure (CNKI), Web of Science, Pharmacopoeia of the Peoples Republic of China, Doctoral and Masters thesis, ancient books, etc. RESULTS Arctii Fructus as an herb used for medicine and food was pervasively distributed and applicated around the world. It was traditionally used to treat anemopyretic cold, dyspnea and cough, sore throat, etc. To date, more than 200 compounds have been isolated and identified from Arctii Fructus. It contained lignans, phenolic acids and fatty acids, terpenoids, volatile oils and others. Lignans, especially arctigenin and arctiin, had the extensive pharmacological effects such as anti-cancer, antiviral, anti-inflammatory activities. The ester derivatives of arctigenin had the anti-cancer, anti-Alzheimers disease and immunity enhancing effects. Although Arctii Fructus extract had no toxicity, arctigenin was toxic at a certain dose. The alleviating effects of Arctii Fructus on chronic inflammation and ageing have been demonstrated by clinical studies. Arctii Fructus is regarded as a worthy herb with many chemical components and various pharmacological effects. Several traditional applications have been supported by modern pharmacological research. However, their action mechanisms need to be further studied. Although many chemical components were isolated from Arctii Fructus, the current research mainly focused on lignans, especially arctiin and arctigenin. Therefore, it is very important to deeply clarify the pharmacological activities and action mechanism of the compounds and make full medicinal use of the resources of Arctii Fructus.

Linking fluid-axons interactions to the macroscopic fluid transport properties of the brain.

Many brain disorders, including Alzheimers Disease and Parkinsons Disease, and drug delivery procedures are linked to fluid transport in the brain yet, while neurons are extremely soft and can be easily deformed, how the microscale channel flow interacts with the neuronal structures (especially axons) deformation and how these interactions affect the macroscale tissue function and transport properties is poorly understood. Misrepresenting these relationships may lead to the erroneous prediction of e.g. disease spread, drug delivery, and nerve injury in the brain. However, understanding fluid-neuron interactions is an outstanding challenge because the behaviours of both phases are not only dynamic but also occur at an extremely small length scale (the width of the flow channel is ∼100 nm), which cannot be captured by state-of-the-art experimental techniques. Here, by explicitly simulating the dynamics of the flow and axons at the microstructural level, we, for the first time, establish the link between micromechanical tissue response to the physical laws governing the macroscopic transport property of the brain white matter. We found that interactions between axons and the interstitial flow are very strong, thus playing an essential role in the brain fluidmass transport. Furthermore, we proposed the first anisotropic pressure-dependent permeability tensor informed by microstructural dynamics for more accurate brain modelling at the macroscale, and analysed the effect of the variation of the microstructural parameters that influence such tensor. These findings will shed light on some unsolved issues linked to brain functions and medical treatments relying on intracerebral transport, and the mathematical model provides a framework to more realistically model the brain and design brain-tissue-like biomaterials. STATEMENT OF SIGNIFICANCE This study reveals how neurons interact with the fluid flowing around them and how these microscale interactions affect macroscale transport behaviour of the brain tissue. The findings provide unprecedented insights into some unsolved issues linked to brain functions and medical treatments relying on intracerebral fluid transport. Furthermore, we, for the first time, established a microstructure-informed permeability tensor as a function of local hydraulic pressure and pressure gradient for the brain tissue, which inherently captures the dynamic transport property of the brain. This study is a cornerstone to advance the predicting accuracy of brain tissue transport property and neural tissue engineering.

Effect of carbonaceous ultrafine particles on the structure and oligomerization of Aβ

The impact of pervasive air pollutants on human health is a growing concern in scientific communities. Among different air pollutants, ultrafine particles (UFPs with aerodynamic diameter <100 nm) might pass through biological barriers and have a severe impact on human health, including early progression of neurodegenerative diseases such as Alzheimers disease (AD). A significant fraction of UFPs consists of carbonaceous compounds, composed of elemental and organic carbon (EC and OC). While in-vivo experimental studies showed the neurotoxicity of typical OC and polycyclic aromatic hydrocarbons (PAHs), the molecular interactions involved in the progression of AD remain unclear. In this study, molecular dynamics simulations were performed to investigate the impact of carbonaceous UFPs on the structure of the Aβ

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition.

Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimers pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We studied 727 participants from the Alzheimers Disease Neuroimaging Initiative with plasma and CSF p-tau181 data, apolipoprotein (APOE) ε4 carrier status, amyloid positron emission tomography (PET) imaging, and neuropsychological data. Higher levels of plasma and CSF p-tau181 were observed among APOE ε4 carriers. CSF and plasma p-tau181 were significantly associated with memory, and this effect was greater in APOE ε4 carriers. However, whereas CSF p-tau181 was not significantly associated with language or attentionexecutive function among ε4 carriers or non-carriers, APOE ε4 status moderated the association of plasma p-tau181 with both language and attentionexecutive function. These findings lend support to the notion that p-tau181 biofluid markers are useful in measuring AD pathologic changes but also suggest that CSF and plasma p-tau181 have unique properties and dynamics that should be considered when using these markers in research and clinical practice.

AI reveals insights into link between CD33 and cognitive impairment in Alzheimers Disease.

Modeling biological mechanisms is a key for disease understanding and drug-target identification. However, formulating quantitative models in the field of Alzheimers Disease is challenged by a lack of detailed knowledge of relevant biochemical processes. Additionally, fitting differential equation systems usually requires time resolved data and the possibility to perform intervention experiments, which is difficult in neurological disorders. This work addresses these challenges by employing the recently published Variational Autoencoder Modular Bayesian Networks (VAMBN) method, which we here trained on combined clinical and patient level gene expression data while incorporating a disease focused knowledge graph. Our approach, called iVAMBN, resulted in a quantitative model that allowed us to simulate a down-expression of the putative drug target CD33, including potential impact on cognitive impairment and brain pathophysiology. Experimental validation demonstrated a high overlap of molecular mechanism predicted to be altered by CD33 perturbation with cell line data. Altogether, our modeling approach may help to select promising drug targets.

Reporting Down syndrome on the death certificate for Alzheimer diseaseunspecified dementia deaths.

Death certificates are crucial for understanding population health trends including the burden of disease mortality. Accurate reporting of causes of death on these records is necessary in order to implement adequate public health policies and fund disease research. While there is evidence that Alzheimer disease and unspecified dementia are prevalent among people with Down syndrome, a 2014 Centers for Disease Control and Prevention (CDC) rule change instructing that Down syndrome should be reported as the underlying cause of death in instances when death occurred from Alzheimer disease or unspecified dementia threatens the accuracy and the utility of death certificates for this population. This study used 15 years (2005-2019) of US death certificate data for adults with and without Down syndrome. We compare the mortality burden due to Alzheimer disease and unspecified dementia prior to and after amending death certificates that report Down syndrome as the underlying cause of death. When analyzing death certificates without addressing the reporting of Down syndrome as the underlying cause of death, rates of death due to Alzheimer disease and dementia ranked as the third leading cause of death for both adults with and without Down syndrome. After amending death certificates that reported Down syndrome as the underlying cause of death, Alzheimer disease and dementia were the leading cause of death among those with Down syndrome, occurring 2.7 times more in adults with compared to without Down syndrome. The findings of this study highlight the importance of accurate mortality data for studying and addressing population health trends. The current practice of reporting Down syndrome as the underlying cause of death rather than the disease responsible for death needs to be reconsidered and modified. If not, people with Down syndrome may be further marginalized within dementia related support and research.

State-Level Indicators of Childhood Educational Quality and Incident Dementia in Older Black and White Adults.

Higher educational attainment is associated with reduced dementia risk, but the role of educational quality is understudied, presenting a major evidence gap, especially as it may contribute to racial inequities. To evaluate the association between state-level educational quality during childhood and dementia risk. This cohort study analyzed longitudinal data collected from January 1, 1997, through December 31, 2019 (23-year follow-up period). The sample comprised members of Kaiser Permanente Northern California (KPNC), a large integrated health care delivery system, who completed an optional survey during 1964-1972. Eligible individuals were US born non-Hispanic Black or non-Hispanic White aged 65 years or older as of January 1, 1996 were still alive and did not have a dementia diagnosis or lapse in KPNC membership greater than 90 days between January 1 and December 31, 1996. Historical state-level administrative indicators of school quality (school term length, student-teacher ratio, and attendance rates) linked to participants using birth state and birth year (with a 6-year lag) and divided into tertiles using the pooled sample. Dementia diagnoses from electronic health records between 1997 and 2019 were analyzed between March 1 and August 31, 2022. The associations of educational quality with incident dementia were estimated using Cox proportional hazards regression models. Among 21 450 KPNC members who participated in the optional survey, individuals born before availability of educational quality records (n 87) and missing educational attainment (n 585) were excluded. The final analytic sample was 20 778 individuals (56.5% women, 43.5% men mean SD age, 74.7 6.5 years 18.8% Black 81.2% White 41.0% with less than high school education). Among Black individuals, 76.2% to 86.1% (vs 20.8%-23.3% of White individuals) attended schools in states in the lowest educational quality tertiles. Highest (vs lowest) educational quality tertiles were associated with lower dementia risk (student-teacher ratio hazard ratio HR, 0.88 95% CI, 0.83-0.94 attendance rates HR, 0.80 95% CI, 0.73-0.88 term length HR, 0.79 95% CI, 0.73-0.86). Effect estimates did not differ by race and were not attenuated by adjustment for educational attainment. In this cohort study, lower state-average educational quality was more common among Black individuals and associated with higher dementia risk. Differential investment in high-quality education due to structural racism may contribute to dementia disparities.

A Novel Continuous-time Hidden Markov Model Based on a Bag of Features Extracted from MR Brain Images for Alzheimers Stage Progression and Detection.

Mounting novel solutions for conspicuous neurodegenerative disorders that grow consistently, such as Alzheimers disease, rely on tracking and identifying disease development, improvement, and progression. Compared to many clinical or survey-based detection methods, early Alzheimers stage detection can be possible through computer-based MR brain images and discrete stochastic processes. In the case of Alzheimers stage progression, the existing models illustrate that the learning problem comprises two issues estimating posterior probabilities of the Alzheimers stage and computing conditioned statistics of the Alzheimers end-stage. The proposed model overcomes these issues by restructuring the estimation problem as EM-centered CT- HMM. This paper proposes a novel framework model with two phases the first phase covers the feature extraction of magnetic resonance imaging based on many computer vision methods known as a collection of bag-of-features (BoF). In the second phase, the EM-centered learning method is used for the continuous-time hidden Markov model (CT-HMM), an efficient approach to modeling Alzheimers disease progression with time and stages. The proposed CT-HMM is implemented with eight Alzheimers stages (source ADNI) to visualize and predict the stage progression of the ADNI MRI dataset. The proposed model reported the transition posterior probability as 0.765 (high to low stage progression) and 0.234 (low to high stage progression). The models accuracy and F1 score are estimated as 97.13 and 96.51, respectively. The proposed models accuracy and evaluation metrics reported higher results in the work on Alzheimers stage progression and prediction.

Longitudinal characterization of circulating extracellular vesicles and small RNA during simian immunodeficiency virus infection and antiretroviral therapy.

Latent infection by human immunodeficiency virus (HIV) hinders viral eradication despite effective antiretroviral treatment (ART). Amongst proposed contributors to viral latency are cellular small RNAs that have also been proposed to shuttle between cells in extracellular vesicles (EVs). Thus, we profiled EV small RNAs during different infection phases to understand the potential relationship between these EV-associated small RNAs and viral infection. A well characterized simian immunodeficiency virus (SIV)macaque model of HIV was used to profile EV-enriched blood plasma fractions harvested during pre-infection, acute infection, latent infectionART treatment, and rebound after ART interruption. Measurement of EV concentration, size distribution, and morphology was complemented with qPCR array for small RNA expression, followed by individual qPCR validations. Iodixanol density gradients were used to separate EV subtypes and virions. Plasma EV particle counts correlated with viral load and peaked during acute infection. However, SIV gag RNA detection showed that virions did not fully explain this peak. EV microRNAs miR-181a, miR-342-3p, and miR-29a decreased with SIV infection and remained downregulated in latency. Interestingly, small nuclear RNA U6 had a tight association with viral load peak. This study is the first to monitor how EV concentration and EV small RNA expression change dynamically in acute viral infection, latency, and rebound in a carefully controlled animal model. These changes may also reveal regulatory roles in retroviral infection and latency.

27-hydroxycholesterol promotes oligodendrocyte maturation Implications for hypercholesterolemia-associated brain white matter changes.

Oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27-OH is transported across the blood-brain barrier. However, the effects of high 27-OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27-OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases. To test this idea, we first investigated the effects of 27-OH in cultured oligodendrocytes and found that it induces cell death of immature O4

APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice.

The Tau protein can be phosphorylated by numerous kinases. In Alzheimers disease (AD) hyperphosphorylated Tau species accumulate as neurofibrillary tangles that constitute a major hallmark of AD. AD is further characterized by extracellular Aβ plaques, derived from the β-amyloid precursor protein APP. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to regulate two major Tau kinases, GSK3β and CDK5 in THY-Tau22 mice, a widely used mouse model of tauopathy. Immunohistochemistry revealed a dramatic increase in pathologically phosphorylated (AT8 and AT180) or misfolded Tau species (MC1) in the hippocampus of THY-Tau22 mice between 3 and 12 months of age. Using a highly sensitive radioactive kinase assay with recombinant human Tau as a substrate and immunoblotting, we demonstrate an increase in GSK3β and CDK5 activity in the hippocampus of THY-Tau22 mice. Interestingly, AAV-mediated intracranial expression of APPsα in THY-Tau22 mice efficiently restored normal GSK3β and CDK5 activity. Western blot analysis revealed upregulation of the CDK5 regulatory proteins p35 and p25, indicating CDK5 hyperactivation in THY-Tau22 mice. Strikingly, AAV-APPsα rescued p25 upregulation to wild-type levels even at stages of advanced Tau pathology. Sarkosyl fractionation used to study the abundance of soluble and insoluble phospho-Tau species revealed increased soluble AT8-Tau and decreased insoluble AT100-Tau species upon AAV-APPsα injection. Moreover, AAV-APPsα reduced misfolded (MC1) Tau species, particularly in somatodendritic compartments of CA1 pyramidal neurons. Finally, we show that AAV-APPsα upregulated PSD95 expression and rescued deficits in spine density of THY-Tau22 mice. Together our findings suggest that APPsα holds therapeutic potential to mitigate Tau-induced pathology.

Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders.

Neurodegeneration is associated with defects in cytoskeletal dynamics and dysfunctions of the vesicular trafficking and sorting systems. In the last few decades, studies have demonstrated that the key regulators of cytoskeletal dynamics are proteins from the Rho family GTPases, meanwhile, the central hub for vesicle sorting and transport between target membranes is the Rab family of GTPases. In this regard, the role of Rho and Rab GTPases in the induction and maintenance of distinct functional and morphological neuronal domains (such as dendrites and axons) has been extensively studied. Several members belonging to these two families of proteins have been associated with many neurodegenerative disorders ranging from dementia to motor neuron degeneration. In this analysis, we attempt to present a brief review of the potential crosstalk between the Rab and Rho family members in neurodegenerative pathologies such as Alzheimers disease (AD), Parkinsons disease (PD), Huntington disease, and amyotrophic lateral sclerosis (ALS).

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimers disease mouse model.

Astrocyte-synapse bi-directional communication is required for neuronal development and synaptic plasticity. Astrocytes structurally interact with synapses using their distal processes also known as leaflets or perisynaptic astrocytic processes (PAPs). We recently showed that these PAPs are retracted from hippocampal synapses, and involved in the consolidation of fear memory. However, whether astrocytic synaptic coverage is affected when memory is impaired is unknown. Here, we describe in detail an electron microscopy method that makes use of a large number of 2D images to investigate structural astrocyte-synapse interaction in paraformaldehyde fixed brain tissue of mice. We show that fear memory-induced synaptic activation reduces the interaction between the PAPs and the presynapse, but not the postsynapse, accompanied by retraction of the PAP tip from the synaptic cleft. Interestingly, this retraction is absent in the APPPS1 mouse model of Alzheimers disease, supporting the concept that alterations in astrocyte-synapse coverage contribute to memory processing.

Current Peptide Vaccine and Immunotherapy Approaches Against Alzheimers Disease.

Peptide vaccines and immunotherapies against aggregating proteins involved in the pathogenesis and progression of Alzheimers disease (AD) - the β-amyloid peptide (Aβ) and tau - are promising therapeutic avenues against AD. Two decades of effort has led to the controversial FDA approval of the monoclonal antibody Aducanumab (Aduhelm), which has subsequentially sparked the revival and expedited review of promising monoclonal antibody immunotherapies that target Aβ. In this review, we explore the development of Aβ and tau peptide vaccines and immunotherapies with monoclonal antibodies in clinical trials against AD.

Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders Evidence from clinical and preclinical studies.

For most, staying mentally sharp as they age is a very high priority that may be thwarted by the consequences of a postoperative complication unrelated to the disorder which necessitated the surgical intervention. Perioperative neurocognitive disorder (PND) is an overarching term for cognitive impairment in surgical patients, that includes conditions from delirium to dementia, affecting more than 7 million patients annually in the US, and which threatens both functional independence and life. Clinical trials and meta-analyses have identified the association between PNDs and increased perioperative levels of Interleukin-6 (IL-6), a pleiotropic cytokine that is both necessary and sufficient for postoperative memory decline in a preclinical model of PND. Recently, we reported that, in adult male wild-type mice subjected to tibial fracture under general anesthesia, IL-6 trans-signaling in hippocampal CA1 neurons mediates surgery-induced memory impairment. As there are no therapeutic options for preventing or reversing PNDs, patients and their caregivers, as well as the healthcare industry, endure staggering costs. Olamkicept, a highly selective IL-6 trans-signaling blocker has shown to be efficacious and safe in clinical trials involving patients with inflammatory bowel disease, another condition for which IL-6 trans-signaling is the mediating mechanism. Subject to a demonstration that olamkicept is effective in preventing cognitive impairment in vulnerable (aged and Alzheimers Disease) preclinical PND models, clinical trials involving aged andor cognitively impaired surgical patients should be undertaken to study olamkicepts utility for PNDs.

Extensive accumulation of misfolded protein aggregates during natural aging and senescence.

Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells,

Efficient Training on Alzheimers Disease Diagnosis with Learnable Weighted Pooling for 3D PET Brain Image Classification.

Three-dimensional convolutional neural networks (3D CNNs) have been widely applied to analyze Alzheimers disease (AD) brain images for a better understanding of the disease progress or predicting the conversion from cognitively impaired (CU) or mild cognitive impairment status. It is well-known that training 3D-CNN is computationally expensive and with the potential of overfitting due to the small sample size available in the medical imaging field. Here we proposed a novel 3D-2D approach by converting a 3D brain image to a 2D fused image using a Learnable Weighted Pooling (LWP) method to improve efficient training and maintain comparable model performance. By the 3D-to-2D conversion, the proposed model can easily forward the fused 2D image through a pre-trained 2D model while achieving better performance over different 3D and 2D baselines. In the implementation, we chose to use ResNet34 for feature extraction as it outperformed other 2D CNN backbones. We further showed that the weights of the slices are location-dependent and the model performance relies on the 3D-to-2D fusion view, with the best outcomes from the coronal view. With the new approach, we were able to reduce 75% of the training time and increase the accuracy to 0.88, compared with conventional 3D CNNs, for classifying amyloid-beta PET imaging from the AD patients from the CU participants using the publicly available Alzheimers Disease Neuroimaging Initiative dataset. The novel 3D-2D model may have profound implications for timely AD diagnosis in clinical settings in the future.

Cardiac MRI to guide heart failure and atrial fibrillation drug discovery a Mendelian randomization analysis.

Background drug development and disease prevention of heart failure (HF) and atrial fibrillation (AF) are impeded by a lack of robust early-stage surrogates. We determined to what extent cardiac magnetic resonance (CMR) measurements act as surrogates for the development of HF or AF in healthy individuals. Methods Genetic data was sourced on the association with 22 atrial and ventricular CMR measurements. Mendelian randomization was used to determine CMR associations with atrial fibrillation (AF), heart failure (HF), non-ischemic cardiomyopathy (CMP), and dilated cardiomyopathy (DCM). Additionally, for the CMR surrogates of AF and HF, we explored their association with non-cardiac traits. Results In total we found that 9 CMR measures were associated with the development of HF, 7 with development of non-ischemic CMP, 6 with DCM, and 12 with AF. biventricular ejection fraction (EF), biventricular or end-systolic volumes (ESV) and left-ventricular (LV) end diastolic volume (EDV) were associated with all 4 cardiac outcomes. Increased LV-MVR (mass to volume ratio) affected HF (odds ratio (OR) 0.83, 95%CI 0.79 0.88), and DCM (OR 0.26, 95%CI 0.20 0.34. We were able to identify 9 CMR surrogates for HF andor AF (including LV-MVR, biventricular EDV, ESV, and right-ventricular EF) which associated with non-cardiac traits such as blood pressure, lung function traits, BMI, cardioembolic stroke, and late-onset Alzheimers disease. Conclusion CMR measurements may act as surrogate endpoints for the development of HF (including non-ischemic CMP and DCM) or AF. Additionally, we show that changes in cardiac function and structure measured through CMR, may affect diseases of other organs leading to lung disease or late-onset Alzheimers disease.

PPAD A deep learning architecture to predict progression of Alzheimers disease.

Alzheimers disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Mild cognitive impairment (MCI) is an intermediary stage between cognitively normal (CN) state and AD. Not all people who have MCI convert to AD. The diagnosis of AD is made after significant symptoms of dementia such as short-term memory loss are already present. Since AD is currently an irreversible disease, diagnosis at the onset of disease brings a huge burden on patients, their caregivers, and the healthcare sector. Thus, there is a crucial need to develop methods for the early prediction AD for patients who have MCI. Recurrent Neural Networks (RNN) have been successfully used to handle Electronic Health Records (EHR) for predicting conversion from MCI to AD. However, RNN ignores irregular time intervals between successive events which occurs common in EHR data. In this study, we propose two deep learning architectures based on RNN, namely Predicting Progression of Alzheimers Disease (PPAD) and PPAD-Autoencoder (PPAD-AE). PPAD and PPAD-AE are designed for early predicting conversion from MCI to AD at the next visit and multiple visits ahead for patients, respectively. To minimize the effect of the irregular time intervals between visits, we propose using age in each visit as an indicator of time change between successive visits. Our experimental results conducted on Alzheimers Disease Neuroimaging Initiative (ADNI) and National Alzheimers Coordinating Center (NACC) datasets showed that our proposed models outperformed all baseline models for most prediction scenarios in terms of F2 and sensitivity. We also observed that the age feature was one of top features and was able to address irregular time interval problem.

Network analysis reveals strain-dependent response to misfolded tau aggregates.

Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimers disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimers disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing Seeding of tau predates the phosphorylation and spreading of tau aggregates. Acri and colleagues report transcriptomic responses to tau and elevated tau seeds in wild-derived mice. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.

Effect of Pathway-specific Polygenic Risk Scores for Alzheimers Disease (AD) on Rate of Change in Cognitive Function and AD-related Biomarkers among Asymptomatic Individuals.

Genetic scores for late-onset Alzheimers disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimers Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. PRS and p-PRSs with and without apolipoprotein E ( We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSsPRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan when In addition to

Path integration selectively predicts midlife risk of Alzheimers disease.

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimers disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

EMBER multi-dimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains.

In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. There is a need to rapidly identify these amyloid conformations

Astrocyte reactivity influences the association of amyloid-β and tau biomarkers in preclinical Alzheimers disease.

An unresolved question for the understanding of Alzheimers disease (AD) pathophysiology is why a significant percentage of amyloid β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration.

Bioinformatic prediction of the molecular links between Alzheimers disease and diabetes mellitus.

Alzheimers disease (AD) and type 2 diabetes mellitus (DM2) are chronic degenerative diseases with complex molecular processes that are potentially interconnected. The aim of this work was to predict the potential molecular links between AD and DM2 from different sources of biological information. In this work, data mining of nine databases (DisGeNET, Ensembl, OMIM, Protein Data Bank, The Human Protein Atlas, UniProt, Gene Expression Omnibus, Human Cell Atlas, and PubMed) was performed to identify gene and protein information that was shared in AD and DM2. Next, the information was mapped to human protein-protein interaction (PPI) networks based on experimental data using the STRING web platform. Then, gene ontology biological process (GOBP) and pathway analyses with EnrichR showed its specific and shared biological process and pathway deregulations. Finally, potential biomarkers and drug targets were predicted with the Metascape platform. A total of 1,551 genes shared in AD and DM2 were identified. The highest average degree of nodes within the PPI was for DM2 (average 2.97), followed by AD (average degree 2.35). GOBP for AD was related to specific transcriptional and translation genetic terms occurring in neurons cells. The GOBP and pathway information for the association AD-DM2 were linked mainly to bioenergetics and cytokine signaling. Within the AD-DM2 association, 10 hub proteins were identified, seven of which were predicted to be present in plasma and exhibit pharmacological interaction with monoclonal antibodies in use, anticancer drugs, and flavonoid derivatives. Our data mining and analysis strategy showed that there are a plenty of biological information based on experiments that links AD and DM2, which could provide a rational guide to design further diagnosis and treatment for AD and DM2.

Extracellular vesicles, the emerging mirrors of brain physiopathology.

Extracellular vesicles are secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Their molecular cargo reflects the physiological processes that their cells of origin are undergoing. Thus, many studies have suggested that extracellular vesicles could be a promising biomarker tool for many diseases, mainly due to their biological relevance and easy accessibility to a broad range of body fluids. Moreover, since their biological composition leads them to cross the blood-brain barrier bidirectionally, growing evidence points to extracellular vesicles as emerging mirrors of brain diseases processes. In this regard, this review explores the biogenesis and biological functions of extracellular vesicles, their role in different physiological and pathological processes, their potential in clinical practice, and the recent outstanding studies about the role of exosomes in major human brain diseases, such as Alzheimers disease (AD), Parkinsons disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or brain tumors.

Testing the knowledge of Alzheimers disease

This study aimed to investigate the knowledge status of Alzheimers disease (AD) among community health service center (CHSC) staff in Jiaxing, China, and to compare the effects of online with offline training. A total of 763 people from 12 community health service centers were investigated using a self-created general situation questionnaire and the Alzheimers Disease Knowledge Scale (ADKS). Among the participants, 261 people who were willing to receive training were randomly divided into two groups according to the institution in which they worked to receive online or offline training, respectively. The average ADKS score was 19.77, and the awareness rate was 65.92% the results for every field were as follows treatment and management (81.32%) life impact (77.76%) disease course (75.23%) assessment and diagnosis (68.94%) risk factors (65.05%) symptoms (57.90%) caregiving (44.06%). Education and profession had impacts on the total ADKS scores ( Community health service center staff in Jiaxing had limited knowledge of AD, particularly in the symptom and caregiving dimensions. One instance of training on AD-related knowledge to some degree helped to improve this but still fell short of meeting the national requirements. No significant differences were found between offline and online training effects.

Methods for the isolation and analysis of Aβ from postmortem brain.

Amyloid β-protein (Aβ) plays an initiating role in Alzheimers disease (AD), but only a small number of groups have studied Aβ extracted from human brain. Most prior studies have utilized synthetic Aβ peptides, but the relevance of these test tube experiments to the conditions that prevail in AD is uncertain. Here, we describe three distinct methods for studying Aβ from cortical tissue. Each method allows the analysis of different ranges of species thus enabling the examination of different questions. The first method allows the study of readily diffusible Aβ with a relatively high specific activity. The second enables the analysis of readily solubilized forms of Aβ the majority of which are inactive. The third details the isolation of true Aβ dimers which have disease-related activity. We also describe a bioassay to study the effects of Aβ on the neuritic integrity of iPSC-derived human neurons. The combined use of this bioassay and the described extraction procedures provides a platform to investigate the activity of different forms and mixtures of Aβ species, and offers a tractable system to identify strategies to mitigate Aβ mediated neurotoxicity.

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimers Disease Experimental and Computational Insights.

Alzheimers disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

Short-term associations between ambient air pollution and emergency department visits for Alzheimers disease and related dementias.

Dementia is a seriously disabling illness with substantial economic and social burdens. Alzheimers disease and its related dementias (ADADRD) constitute about two-thirds of dementias. ADADRD patients have a high prevalence of comorbid conditions that are known to be exacerbated by exposure to ambient air pollution. Existing studies mostly focused on the long-term association between air pollution and ADADRD morbidity, while very few have investigated short-term associations. This study aims to estimate short-term associations between ADADRD emergency department (ED) visits and three common air pollutants fine particulate matter (PM For the period 2005 to 2015, we analyzed over 7.5 million ADADRD ED visits in five US states (California, Missouri, North Carolina, New Jersey, and New York) using a time-stratified case-crossover design with conditional logistic regression. Daily estimated PM The most consistent positive association was found for NO Our results suggest ADADRD patients are vulnerable to short-term health effects of ambient air pollution and strategies to lower exposure may reduce morbidity.

Neuroprotective Effects of a Multi-Herbal Extract on Axonal and Synaptic Disruption

Alzheimers disease (AD) is a multifactorial disorder characterized by cognitive decline. Current available therapeutics for AD have limited clinical benefit. Therefore, preventive therapies for interrupting the development of AD are critically needed. Molecules targeting multifunction to interact with various pathlogical components have been considered to improve the therapeutic efficiency of AD. In particular, herbal medicines with multiplicity of actions produce cognitive benefits on AD. Bugu-M is a multi-herbal extract composed of To evaluate the potential of Bugu-M on amyloid-β (Aβ) toxicity and its We illustrated the effect of Bugu-M on Aβ In primary cortical neuronal cultures, Bugu-M mitigated Aβ-evoked toxicity by reducing cytoskeletal aberrations and axonal disruption, restoring presynaptic and postsynaptic protein expression, suppressing mitochondrial damage and apoptotic signaling, and reserving neurogenic and neurotrophic factors. Importantly, 30-day administration of Bugu-M effectively prevented development of cognitive impairment in 3-month-old female 3×Tg-AD mice. Bugu-M might be beneficial in delaying the progression of AD, and thus warrants consideration for its preventive potential for AD.

The Amyloid Cascade Hypothesis 2.0 Generalization of the Concept.

Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimers disease (AD) is driven by

A Case of Minimally Progressive Prodromal Alzheimers Disease.

Prodromal Alzheimers disease (AD) is a neurodegenerative condition typically progressing to dementia within 3 years. We describe a case of a mild cognitive impairment (MCI) patient with biomarker evidence for amyloidosis, tau, and neurodegeneration who had minimal changes in clinical phenotype during an 11-year period. AD biomarkers were obtained with cerebrospinal fluid analysis and amyloid PET imaging, both of which supported a biological diagnosis of AD. However, the patients neuropsychological profile remained stable over 11 years except for mild memory-retrieval changes. This case provides evidence that MCI with supportive AD biomarkers may have an atypically minimal progression.

Development of digital voice biomarkers and associations with cognition, cerebrospinal biomarkers, and neural representation in early Alzheimers disease.

Advances in natural language processing (NLP), speech recognition, and machine learning (ML) allow the exploration of linguistic and acoustic changes previously difficult to measure. We developed processes for deriving lexical-semantic and acoustic measures as Alzheimers disease (AD) digital voice biomarkers. We collected connected speech, neuropsychological, neuroimaging, and cerebrospinal fluid (CSF) AD biomarker data from 92 cognitively unimpaired (40 Aβ) and 114 impaired (63 Aβ) participants. Acoustic and lexical-semantic features were derived from audio recordings using ML approaches. Lexical-semantic (area under the curve AUC 0.80) and acoustic (AUC 0.77) scores demonstrated higher diagnostic performance for detecting MCI compared to Boston Naming Test (AUC 0.66). Only lexical-semantic scores detected amyloid-β status ( These preliminary findings suggest that derived digital biomarkers may identify cognitive impairment in preclinical and prodromal AD, and may predict disease progression. This study derived lexical-semantic and acoustics features as Alzheimers disease (AD) digital biomarkers.These features were derived from audio recordings using machine learning approaches.Voice biomarkers detected cognitive impairment and amyloid-β status in early stages of AD.Voice biomarkers may predict Alzheimers disease progression.These markers significantly mapped to functional connectivity in AD-susceptible brain regions.

A data-driven examination of apathy and depressive symptoms in dementia with independent replication.

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathydepression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathydepression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy We found four classes no symptoms, apathy, depression and apathydepression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

Health equity considerations in pragmatic trials in Alzheimers and dementia disease Results from a methodological review.

To improve dementia care delivery for persons across all backgrounds, it is imperative that health equity is integrated into pragmatic trials. We reviewed 62 pragmatic trials of people with dementia published 2014 to 2019. We assessed health equity in the objectives design, conduct, analysis and reporting using PROGRESS-Plus which stands for Place of residence, Raceethnicity, Occupation, Gendersex, Religion, Education, Socioeconomic status, Social capital, and other factors such as age and disability. Two (3.2%) trials incorporated equity considerations into their objectives nine (14.5%) engaged with communities 4 (6.5%) described steps to increase enrollment from equity-relevant groups. Almost all trials (59, 95.2%) assessed baseline balance for at least one PROGRESS-Plus characteristic, but only 10 (16.1%) presented subgroup analyses across such characteristics. Differential recruitment, attrition, implementation, adherence, and applicability across PROGRESS-Plus were seldom discussed. Ongoing and future pragmatic trials should more rigorously integrate equity considerations in their design, conduct, and reporting. Few pragmatic trials are explicitly designed to inform equity-relevant objectives.Few pragmatic trials take steps to increase enrollment from equity-relevant groups.Disaggregated results across equity-relevant groups are seldom reported.Adherence to existing tools (e.g., IMPACT Best Practices, CONSORT-Equity) is key.

A meta-analysis investigating the relationship between inflammation in autoimmune disease, elevated CRP, and the risk of dementia.

Alzheimers Disease (AD) represents the most common type of dementia and is becoming a steadily increasing challenge for health systems globally. Inflammation is developing as the main focus of research into Alzheimers disease and has been demonstrated to be a major driver of the pathologies associated with AD. This evidence introduces an interesting research question, whether chronic inflammation due to pathologies such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) could lead to a higher risk of developing dementia. In both IBD and RA, increased levels of the inflammatory biomarker C-reactive protein (CRP) can be highlighted, the latter being directly implicated in neuroinflammation and AD. In this meta-analysis both the association between chronic inflammatory diseases and elevated levels of CRP during midlife were investigated to examine if they correlated with an augmented risk of dementia. Moreover, the association between increased CRP and modifications in the permeability of the Blood Brain Barrier (BBB) in the presence of CRP is explored. The results displayed that the odds ratio for IBD and dementia was 1.91 1.15-3.15, for RA it was 1.90 1.09-3.32 following sensitivity analysis and for CRP it was 1.62 1.22-2.15. These results demonstrate a higher risk of dementia in patients presenting chronic inflammation and that exists an independent association with high CRP in midlife. This paper builds on published research that suggest a critical role for CRP both in stroke and AD and provides an analysis on currently published research on multiple diseases (IBD and RA) in which CRP is raised as well as chronically elevated. CRP and the associated risk of dementia and further research indicated that the monomeric form of CRP can infiltrate the BBBbe released from damaged micro-vessels to access the brain. This meta-analysis provides first-time evidence that chronic elevation of CRP in autoimmune diseases is directly associated with an increased risk of later development of Alzheimers disease. Therefore, greater priority should be provided to the effective control of inflammation in patients with chronic inflammatory or autoimmune conditions and further long-term assessment of circulating CRP might inform of an individuals relative risk of developing dementia.

Diagnostic models and predictive drugs associated with cuproptosis hub genes in Alzheimers disease.

Alzheimers disease (AD) is a chronic neurodegenerative disease, and its underlying genes and treatments are unclear. Abnormalities in copper metabolism can prevent the clearance of β-amyloid peptides and promote the progression of AD pathogenesis. Therefore, the present study used a bioinformatics approach to perform an integrated analysis of the hub gene based on cuproptosis that can influence the diagnosis and treatment of AD. The gene expression profiles were obtained from the Gene Expression Omnibus database, including non-demented (ND) and AD samples. A total of 2,977 cuproptosis genes were retrieved from published articles. The seven hub genes associated with cuproptosis and AD were obtained from the differentially expressed genes and WGCNA in brain tissue from GSE33000. The GO analysis demonstrated that these genes were involved in phosphoribosyl pyrophosphate, lipid, and glucose metabolism. By stepwise regression and logistic regression analysis, we screened four of the seven cuproptosis genes to construct a diagnostic model for AD, which was validated by GES15222, GS48350, and GSE5281. In addition, immune cell infiltration of samples was investigated for correlation with these hub genes. We identified six drugs targeting these seven cuproptosis genes in DrugBank. Hence, these cuproptosis gene signatures may be an important prognostic indicator for AD and may offer new insights into treatment options.

Patients with Alzheimers disease dementia show partially preserved parietal hubs modeled from resting-state alpha electroencephalographic rhythms.

Graph theory models a network by its nodes (the fundamental unit by which graphs are formed) and connections. Degree hubs reflect node centrality (the connection rate), while connector hubs are those linked to several clusters of nodes (mainly long-range connections). Here, we compared hubs modeled from measures of interdependencies of between-electrode resting-state eyes-closed electroencephalography (rsEEG) rhythms in normal elderly (Nold) and Alzheimers disease dementia (ADD) participants. At least 5 min of rsEEG was recorded and analyzed. As ADD is considered a network disease and is typically associated with abnormal rsEEG delta (<4 Hz) and alpha rhythms (8-12 Hz) over associative posterior areas, we tested the hypothesis of abnormal posterior hubs from measures of interdependencies of rsEEG rhythms from delta to gamma bands (2-40 Hz) using eLORETA bivariate and multivariate-directional techniques in ADD participants versus Nold participants. Three different definitions of connector hub were used. Convergent results showed that in both the Nold and ADD groups there were significant parietal degree and connector hubs derived from alpha rhythms. These hubs had a prominent outward directionality in the two groups, but that directionality was lower in ADD participants than in Nold participants. In conclusion, independent methodologies and hub definitions suggest that ADD patients may be characterized by low outward directionality of partially preserved parietal degree and connector hubs derived from rsEEG alpha rhythms.

Targeting IGF1R signaling for brain aging and Alzheimers disease.

The role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. Because it was shown that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, it was of interest to investigate this relationship in brain aging. We used CRISPR technology to develop a mouse model with targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1R

The roles of fungus in CNS autoimmune and neurodegeneration disorders.

Fungal infection or proliferation in our body is capable of initiation of strong inflammation and immune responses that result in different consequences, including infection-trigged organ injury and inflammation-related remote organ dysfunction. Fungi associated infectious diseases have been well recognized in the clinic. However, whether fungi play an important role in non-infectious central nervous system disease is still to be elucidated. Recently, a growing amount of evidence point to a non-negligible role of peripheral fungus in triggering unique inflammation, immune response, and exacerbation of a range of non-infectious CNS disorders, including Multiple sclerosis, Neuromyelitis optica, Parkinsons disease, Alzheimers disease, and Amyotrophic lateral sclerosis et al. In this review, we summarized the recent advances in recognizing patterns and inflammatory signaling of fungi in different subsets of immune cells, with a specific focus on its function in CNS autoimmune and neurodegeneration diseases. In conclusion, the fungus is capable of triggering unique inflammation by multiple mechanisms in the progression of a body of CNS non-infectious diseases, suggesting it serves as a key factor and critical novel target for the development of potential therapeutic strategies.

Aberrant Energy Metabolism in Alzheimers Disease.

To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimers disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repairregenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

A review article on neuroprotective, immunomodulatory, and anti-inflammatory role of vitamin-D3 in elderly COVID-19 patients.

Vitamin D3 is a secosteroid, broad-spectrum immunomodulatory, antioxidant, and anti-inflammatory hormone produced either by the internal subcutaneous pathway in the presence of ultraviolet B (UVB) rays or by the external pathway in the form of supplements. Vitamin D3 deficiency is a common and reversible contributor to mortality and morbidity among critically ill patients, including Coronavirus Disease 2019 (COVID-19) and other viral infections. The major functions of vitamin D3 are inhibiting the proinflammatory pathways, including nuclear factor kappa B (NF-kB), inflammatory cytokines, such as interleukin-6 (ILs-6), interleukin-18 (ILs-18), and tumour necrosis factor (TNF), preventing the loss of neural sensation in COVID-19, maintaining respiratory homeostasis, and acting as an antiviral, antimalarial, and antihypertensive agent. Vitamin D3 has an important role in reversing the COVID-19 infection in patients who have previously suffered from a neurological disease, such as Alzheimers disease, Parkinson disease, motor neuron disease, multiple sclerosis, Creutzfeldt-Jakob disease, stroke, cardiovascular problems, headache, sleep-associated disorder, and others. Moreover, vitamin D3 plays a key role in regulating the gene expression of different pro-inflammatory cytokines. In addition to the information provided above, the current review article provides the most recent information on Vitamin D against COVID-19 with comorbid neurological disorders. Furthermore, we present the most recent advancement and molecular mechanism of action of vitamin D3. Diabetes, cardiovascular disease, and neurological disorders are comorbid conditions, and vitamin D3 is a critical regulator of COVID-19 infection during these conditions. In the midst of the COVID-19 epidemic, factors such as sex, latitudes, nutrition, demography, pollution, and gut microbiota warrants for additional research on vitamin D supplements.

Neuropsychiatric Symptoms and Caregiver Stress in Parkinsons Disease with Cognitive Impairment, Alzheimers Disease, and Frontotemporal Dementia.

A better understanding of factors associated with caregiver burden might facilitate the construction of coping strategies to improve their clinical outcomes and the comprehensive care model for dementia. To investigate the cognitive and neuropsychiatric domains that contribute to caregiver burden in three types of neurodegenerative disorders Parkinsons disease (PD), Alzheimers disease (AD), and frontotemporal disease (FTD). Eight hundred and fourteen patients and their caregivers were invited to participate among them, 235 had PD with cognitive impairment 429 had AD, and 150 had FTD. The evaluation protocol included the Neuropsychiatric Inventory (NPI), the Mini-Mental State Examination, the Chinese Version Verbal Learning Test, the modified Trail Making Test B, semantic fluency, and a geriatric depression score. Statistical comparisons of the cognitive tests, NPI total scores, and caregiver burden among the three diagnosed types of dementia, matched for a Clinical Dementia Rating (CDR) of 0.5 or 1, were performed, and multivariate linear regression models were used to evaluate the parameter significance. Caregivers for patients with PD and FTD showed significant burden increments when the CDR scores changes from 0.5 to 1. For CDR 0.5, the PD group had significantly lower caregiver burdens than the AD group, but the NPI total scores were significantly higher. Factors related to caregiver burden were the presence of delusion among all diagnosis groups, while the impact of NPI total scores related to caregiver burden was the highest in FTD, followed by AD and PD. At the mild to moderate stages, our results suggested different degrees of significance in terms of the cognitive test scores or NPI subdomains for predicting caregiver stress among the three types of dementia.

Mortality Risks and Causes of Death by Dementia Types in a Japanese Cohort with Dementia NCGG-Stories.

Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease. We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort. The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9 female, 1,953) was classified into six groups normal cognition (NC), mild cognitive impairment (MCI), Alzheimers disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC. Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks 2.61-5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ɛ4 allele. Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking.

Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimers Disease A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study.

Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimers disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. To investigate the safety, feasibility, and exploratory measures of efficacy. This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n 32 activeplacebo), and subsequently patients with mild-to-moderate AD (n 56, activeplacebo). Participants were randomized 11 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean -2.61.5, SD 6.586.53, activeplacebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean 0.34-2.03, SD 3.261.18, activeplacebo), and the ventricular volume active group (mean -0.362.50, SD 1.892.05, activeplacebo), compared to placebo. Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Mitochondria Profoundly Influence Apolipoprotein E Biology.

Mitochondria can trigger Alzheimers disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE apoE) is not well known. Consider whether and how mitochondrial biology influences APOE and apoE biology. We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells) acute, partial mtDNA depletion and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence APOE expression. SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the CEBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels. Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD.

The PI3KAKT Signaling Pathway and Caspase-3 in Alzheimers Disease Which One Is the Beginner

One of the main players in apoptosis during Alzheimers disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimers disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3KAKT signaling pathway. This commentary tries to highlight the probable relations between PI3KAKT signaling pathway and caspase-3 in Alzheimers disease.

Characteristics of Subjective Cognitive Decline Associated with Alzheimers Disease Amyloid Pathology Findings from The CABLE Study.

Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimers disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. We aimed to explore the associations between SCD characteristics with amyloid pathology. Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among individuals with SCD. A total of 535 SCD individuals with available CSF Aβ 42 information from the Chinese Alzheimers Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI 2.00, 1.19-3.36), subthreshold depressive symptoms (OR, 95% CI 2.31, 1.05-5.09), and subthreshold anxiety symptoms (OR, 95% CI 2.22, 1.09-4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ɛ4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD.

Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-β Levels in Alzheimers Disease The Chongqing Ageing Dementia Study.

The kidney-brain crosstalk has been involved in Alzheimers disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR were positively associated with Aβ 42, Aβ 40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ 42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ 42. Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

The Role of Interferon-α in Neurodegenerative Diseases A Systematic Review.

Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs. This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-α in neurodegenerationNDs. Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search. A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production. The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α. Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated.

Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition.

Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimers disease (AD), suggesting that the IL-33ST2 signaling pathway may be implicated in neurodegenerative diseases. To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinsons disease (PD). Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

Multiple Adipokines Predict Dementia Severity as Measured by δ Replication Across Biofluids and Cohorts.

We have explored dementias blood-based protein biomarkers in the Texas Alzheimers Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum plasma). We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., Adipokines. We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype δ in structural equation models (SEM). Significant factor loadings and Adipokines association with δ were replicated across biofluids in the Alzheimers Disease Neuroimaging Initiative (ADNI). Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δs variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROCAUC) for discrimination of Alzheimers disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementias variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs.

Sarm1 Regulates Circadian Rhythm Disorder in Alzheimers Disease in Mice.

Sarm1 (Sterile alpha and TIR motif-containing 1) is a key protein that regulates neurodegenerative pathologies. Alzheimers disease (AD) is highly associated with neurodegenerative lesions and biorhythmic disturbances. This study aims to decipher the role of Sarm1 in AD-induced circadian rhythm disturbances and AD progression. Open field and water maze tests were used to assess the cognitive function of mice. Thioflavin-S staining was used to assess amyloid-β (Aβ) plaque deposition in the hippocampus and cortex. Rhythmic waveform of home cage activity and temperature was recorded to evaluate circadian rhythm. Expression of clock molecules including Bmal1 and Per2 in the hippocampus were analyzed using western blot and real-time PCR. Further, HT22 cells with Sam1 knockout were treated with Aβ 31-35 treatment to initiate circadian rhythm disorder in the cellular level to assess the changes in Bmal1 and Per2. Our data suggested that Sarm1 deficiency rescued cognitive disorder, decreased Aβ plaque deposition in the hippocampus and cortex, inhibited astrocyte activation, improved circadian rhythm, altered clock molecule expression in the cortex and hippocampus in APPPS1 mice. Sarm1 attenuates circadian rhythm disturbances and reduces AD progression. These data support the potential use of Sarm1 as a therapeutic target to improve circadian rhythm to impede AD progression.

Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimers Disease.

Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimers disease (AD) or DLB and had autopsy confirmed diagnosis. The study included 58 participants clinically diagnosed with mild dementia at study entry (AD n 44, DLB n 14) and also had autopsy-confirmed diagnoses of pure AD (n 32), mixed ADLewy body (LB) (n 5), or pure LB (n 11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patients cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed ADLB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed ADLB ($23,592±3,679) dwarfed other groups. Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed ADLB pathology compared to those with pure-AD and pure-DLB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs.

Acupuncture Therapy on Dementia Explained with an Integrated Analysis on Therapeutic Targets and Associated Mechanisms.

Dementia, mainly Alzheimers disease (AD) and vascular dementia (VaD), remains a global health challenge. Previous studies have demonstrated the benefits of acupuncture therapy (AT) in improving dementia. Nevertheless, the therapeutic targets and integrated biological mechanisms involved remain ambiguous. To identify therapeutic targets and biological mechanisms of AT in treating dementia by integrated analysis strategy. By the identification of differentially expressed genes (DEGs) of AD, VaD, and molecular targets of AT active components, the acupuncture therapeutic targets associated with the biological response to AD and VaD were extracted. Therapeutic targets-based functional enrichment analysis was conducted, and multiple networks were constructed. AT-therapeutic crucial targets were captured by weighted gene co-expression network analysis (WGCNA). The interactions between crucial targets with AT active components were verified by molecular docking. Our results demonstrated that 132 and 76 acupuncture therapeutic targets were associated with AD and VaD. AT-therapeutic crucial targets including 58 for AD and 24 for VaD were captured by WGCNA, with 11 in shared, including NMU, GRP, TAC1, ADRA1D, and SST. In addition, 35 and 14 signaling pathways were significantly enriched by functional enrichment analysis, with 6 mutual pathways including neuroactive ligand-receptor interaction, GABAergic synapse, calcium signaling pathway, cAMP signaling pathway, chemokine signaling pathway, and inflammatory mediator regulation of TRP channels. The improvement of AD and VaD by AT was associated with modulation of synaptic function, immunity, inflammation, and apoptosis. Our study clarified the therapeutic targets of AT on dementia, providing valuable clues for complementing and combining pharmacotherapy.

Cerebrospinal Fluid Panel of Synaptic Proteins in Cerebral Amyloid Angiopathy and Alzheimers Disease.

Alzheimers disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. We therefore aimed to investigate synaptic dysfunction in CAA. Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAAATN n 6) were similar to AD patients, while levels in CAAATN- (n 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

Longitudinal Spatial Relationships Between Atrophy and Hypometabolism Across the Alzheimers Disease Continuum.

The ATN framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined ATN groups is currently unclear. To determine the regions of association between atrophy and hypometabolism in ATN groups both within and across time points. We examined multivariate multimodal neuroimaging relationships between MRI and 18FDG-PET among suspected non-Alzheimers disease pathology (SNAP) (A-TN n 14), Amyloid Only (AT-N- n 24) and Probable AD (ATN n 77) groups. Sparse canonical correlation analyses were employed to model spatially disjointed regions of association between MRI and 18FDG-PET data. These relationships were assessed at three combinations of time points -cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up. In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12. These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration.

Impact of Hearing Aids on Progression of Cognitive Decline, Depression, and Quality of Life Among People with Cognitive Impairment and Dementia.

Hearing loss is common in people with dementia (PwD) and a modifiable risk factor for cognitive decline. Recent studies revealed that hearing loss could cause social isolation and depression, which is associated with health-related quality of life (HRQoL). However, there is a lack of knowledge about the impact of the utilization of hearing aids on these outcomes. To assess whether hearing aids use might be positively associated with the progression of cognitive function, depression, and HRQoL among PwD. We analyzed two-year follow-up data from 258 PwD (≥70 years, living at home). Cognitive decline was measured with Mini-Mental Status Examination (MMSE), depression using Geriatric Depression Scale (GDS), and HRQoL with Quality of Life in Alzheimers Disease Scale (QoL-AD). The impact of hearing aid utilization on the progression of outcomes was assessed using multivariate regression models. 123 patients had hearing loss (47.7%), from which n 54 (43.9%) used hearing aids. Patients with hearing loss were older and had a lower HRQoL than those without hearing loss. Use of hearing aids in patients with hearing loss was associated with a lower increase in symptoms (b -0.74, CI95 -1.46 --0.01, p 0.047) over time as compared to those not using hearing aids. There was no effect on PwDs cognition, and the association with higher HRQoL was significant after one, but not consistently over two years. Early detection and intervention of presbycusis using hearing aids might improve mental health and HRQoL in dementia.

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET Two Putative Astrocyte Reactivity Biomarkers for Alzheimers Disease.

Astrocyte reactivity is an early event along the Alzheimers disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Plasma GFAP and Aβ were measured using the Simoa ® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest. Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ 4240 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

Genetic Liability, Exposure Severity, and Post-Traumatic Stress Disorder Predict Cognitive Impairment in World Trade Center Responders.

There is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimers disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown. In a study of 3,997 WTC responders, polygenic scores for Alzheimers disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 911 exposure severity, including symptoms of PTSD. Polygenic scores for Alzheimers disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimers disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors. These results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimers disease, as genetic liability for Alzheimers disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts.

The Generalizability of Longitudinal Changes in Speech Before Alzheimers Disease Diagnosis.

Language impairment in Alzheimers disease (AD) has been widely studied but due to limited data availability, relatively few studies have focused on the longitudinal change in language in the individuals who later develop AD. Significant differences in speech have previously been found by comparing the press conference transcripts of President Bush and President Reagan, who was later diagnosed with AD. In the current study, we explored whether the patterns previously established in the single AD-healthy control (HC) participant pair apply to a larger group of individuals who later receive AD diagnosis. We replicated previous methods on two larger corpora of longitudinal spontaneous speech samples of public figures, consisting of 10 and 9 AD-HC participant pairs. As we failed to find generalizable patterns of language change using previous methodology, we proposed alternative methods for data analysis, investigating the benefits of using different language features and their change with age, and compiling the single features into aggregate scores. The single features that showed the strongest results were moving average typetoken ratio (MATTR) and pronoun-related features. The aggregate scores performed better than the single features, with lexical diversity capturing a similar change in two-thirds of the participants. Capturing universal patterns of language change prior to AD can be challenging, but the decline in lexical diversity and changes in MATTR and pronoun-related features act as promising measures that reflect the cognitive changes in many participants.

The Differential Effects of Apoeɛ4 on Cerebral Volumetric Structures in Different Lifespan in Community-Dwelling Populations.

Apolipoprotein E (APOE) is closely related to Alzheimers disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. We explored the age-related effect of APOE on brain volumes in a community-dwelling cohort. Inhabitants in Shunyi District in Beijing aged≥35 years were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. Neuroimaging small vessel disease characteristics and brain volumes (global measures, cerebral lobes, hippocampus, brainstem, and subcortical nuclei) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOEɛ3ɛ3 carriers account for 71.8%, ɛ2 () 14.0%, and ɛ4 () 14.2%. Compared with APOEɛ3ɛ3, a significant protective effect for APOEɛ4 () on brain parenchyma fraction (β 0.450, p 0.048) was observed in subjects aged≤60 years in participants aged > 60 years, a negative effect for APOEɛ4 () on hippocampus (β 1.087, p 0.021) was found. Our study reveals that APOEɛ4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy.

The Association Between Temporal Atrophy and Episodic Memory Is Moderated by Education in a Multi-Center Memory Clinic Sample.

Cognitive reserve (CR) is hypothesized to partially explain the discrepancy between Alzheimers disease related brain pathology and cognitive performance. Educational attainment is often used as a proxy for CR. To examine the association of years of education and the relationship between atrophy in the medial temporal lobe and episodic memory, in a cross-sectional ecological multi-center memory clinic cohort. Included patients (n 702) had undergone memory clinic examination and were diagnosed with subjective cognitive impairment (n 99), mild cognitive impairment (n 471), or dementia (n 132). Total years of education were used as a moderating variable and neuropathology was operationalized as visual ratings of medial temporal lobe atrophy (MTA) on magnetic resonance imaging and computer tomography images. Weighted least squares regression and multiple regression were used to analyze moderation and the effect of education separately by diagnostic group. A composite score of two episodic memory tests constituted the dependent variable. After controlling for age and gender the interaction term between MTA and years of education was significant indicating moderation. In particular, the regression model showed that at low levels of MTA, high education individuals had better episodic memory performance. However, at higher MTA levels, high education individuals had the lowest episodic memory performance. Education had a significant positive effect on episodic memory in SCI and MCI, but not dementia. These results extend the findings of education moderating the effect of MTA on cognition to a naturalistic memory clinic setting. Implications of the findings for theories on CR are discussed.

Machine Learning Selection of Most Predictive Brain Proteins Suggests Role of Sugar Metabolism in Alzheimers Disease.

The complex and not yet fully understood etiology of Alzheimers disease (AD) shows important proteopathic signs which are unlikely to be linked to a single protein. However, protein subsets from deep proteomic datasets can be useful in stratifying patient risk, identifying stage dependent disease markers, and suggesting possible disease mechanisms. The objective was to identify protein subsets that best classify subjects into control, asymptomatic Alzheimers disease (AsymAD), and AD. Data comprised 6 cohorts 620 subjects 3,334 proteins. Brain tissue-derived predictive protein subsets for classifying AD, AsymAD, or control were identified and validated with label-free quantification and machine learning. A 29-protein subset accurately classified AD (AUC 0.94). However, an 88-protein subset best predicted AsymAD (AUC 0.85) or Control (AUC 0.89) from AD (AUC 0.96). AD versus Control APP, DHX15, NRXN1, PBXIP1, RABEP1, STOM, and VGF. AD versus AsymAD ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PKAR1B. AsymAD versus Control APP, C4A, DMXL1, EXOC2, PITPNB, REBEP1, and VGF. Additional predictors DNAJA3, PTBP2, SLC30A9, VAT1L, CROCC, PNP, SNCB, PRKAR1B, ENPP6, HAPLN2, PSMD4, and CMAS. Biomarkers were dynamically separable across disease stages. Predictive proteins were significantly enriched to sugar metabolism.

PM2.5 and Dementia in a Low Exposure Setting The Influence of Odor Identification Ability and APOE.

Growing evidence show that long term exposure to air pollution increases the risk of dementia. The aim of this study was to investigate associations between PM2.5 exposure and dementia in a low exposure area, and to investigate the role of olfaction and the APOE ɛ4 allele in these associations. Data were drawn from the Betula project, a longitudinal study on aging, memory, and dementia in Sweden. Odor identification ability was assessed using the Scandinavian Odor Identification Test (SOIT). Annual mean PM2.5 concentrations were obtained from a dispersion-model and matched at the participants residential address. Proportional hazard regression was used to calculate hazard ratios. Of 1,846 participants, 348 developed dementia during the 21-year follow-up period. The average annual mean PM2.5 exposure at baseline was 6.77μgm3, which is 1.77μgm3 above the WHO definition of clean air. In a fully adjusted model (adjusted for age, sex, APOE, SOIT, cardiovascular diseases and risk factors, and education) each 1μgm3 difference in annual mean PM2.5-concentration was associated with a hazard ratio of 1.23 for dementia (95% CI 1.01-1.50). Analyses stratified by APOE status (ɛ4 carriers versus non-carriers), and odor identification ability (high versus low), showed associations only for ɛ4 carriers, and for low performance on odor identification ability. PM2.5 was associated with an increased risk of dementia in this low pollution setting. The associations between PM2.5 and dementia seemed stronger in APOE carriers and those with below average odor identification ability.

A Novel Method of Teaching English to People with Mild Cognitive Impairment Using Songs A Randomized Controlled Trial Protocol.

People with mild cognitive impairment (MCI) need to prevent the further decline of their cognitive functions, and one way to do so is by learning a foreign language. This study describes the development of a protocol for a novel, non-pharmacological intervention for people with MCI that seeks to prevent or reduce cognitive decline by teaching English through songs. The development of this protocol follows a mixed-methodology approach, consisting of three stages 1) development of the protocol of the intervention, 2) a randomized controlled trial study with two arms over six months that includes an intervention group and a control group, and 3) the evaluation of the protocol by trainers. In the second stage, we recruited a total of 128 people with MCI from the five participating countries of this study (Greece, Spain, Croatia, Slovenia, and Italy). This educational program will assess three main outcomes after 6 months of the English Lessons with the Use of Songs for People with Mild Cognitive Impairment (E.L.So.M.C.I.) workshops. Our primary outcome will hopefully be an improvement in general cognition in the intervention group compared to the control group from baseline to 6 months follow-up. Secondary outcomes include a decrease in participants anxiety and depression and an improvement in their quality of life. Development of English language skills is the third outcome.

Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases.

Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large-scale manufacturing of therapeutic-grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases. To address these challenges, a strategic workshop with multidisciplinary experts in EV biology and U.S. Food and Drug Administration (USFDA) officials was convened by the National Heart, Lung and Blood Institute. The presentations and discussions were focused on summarizing the current state of science and technology for engineering therapeutic EVs for HLBS diseases, identifying critical knowledge gaps and regulatory challenges and suggesting potential solutions to promulgate translation of therapeutic EVs to the clinic. Benchmarks to meet the critical quality attributes set by the USFDA for other cell-based therapeutics were discussed. Development of novel strategies and approaches for scaling-up EV production and the quality controlquality analysis (QCQA) of EV-based therapeutics were recognized as the necessary milestones for future investigations.

The Effects of Age, Genotype, and Diet on Hippocampal Subfield Iron Dysregulation and Alzheimers Disease Biomarkers in an ApoE Mouse Model.

Current theories regarding accumulation of Alzheimers Disease-related deposits of abnormal intra- and extracellular proteins include reactions to inflammation and mitochondrial dysfunction. In this study we explored whether age, genotype, and inflammation via diet have a greater effect on dysregulatory protein accumulation in any particular subfield of the hippocampus. We stained for ferritin, ferroportin, hyper-phosphorylated tau, and β-amyloid proteins in the hippocampal region of Apolipoprotein E2 (ApoE2), ApoE3, or ApoE4 mice fed a control diet or a hypothesized inflammation-inducing methionine diet and euthanized at 3, 6, 9, or 12 months. We analyzed stains based on hippocampal subfield and compared the protein accumulation levels within each group. We found significantly decreased ferritin expression in ApoE4 mice in the CA1 and Hi regions, and decreased ferroportin expression in ApoE4 mice in the Hi region. There was also a significant effect on hyper-phosphorylated tau protein levels based upon a given mouse genotype and diet interaction. Additionally, there were non-significant trends in each hippocampal subfield of increasing ferroportin and hyper-phosphorylated tau after 6 months of age, and decreasing β-amyloid and ferritin with age. This study identified that there are changes in iron regulatory molecules based on genotype in the Hi and CA1 regions. Our findings also suggest a diet-genotype interaction which affects levels of specific Alzheimers Disease biomarkers in the hippocampus. Additionally, we identified a trend toward increased ability to clear β-amyloid, and decreased ability to clear hyper-phosphorylated tau with age in all subfields, in addition to evidence of increasing iron load with time.

Stress and the risk of Alzheimer dementia Can deconstructed engrams be rebuilt

The exact neuropathological mechanism by which the dementia process unfolds is under intense scrutiny. The disease affects about 38 million people worldwide, 70% of which are clinically diagnosed with Alzheimers disease (AD). If the destruction of synapses essential for learning, planning and decision-making is part of the problem, must the restoration of previously lost synapses be part of the solution It is plausible that neuronal capacity to restitute information corresponds with the adaptive capacity of its connectivity reserve. A challenge will be to promote the functional connectivity that can compensate for the lost one. This will require better clarification of the remodeling of functional connectivity during the progression of AD dementia and its reversal upon experimental treatment. A major difficulty is to promote the neural pathways that are atrophied in AD dementia while suppressing others that are bolstered. Therapeutic strategies should aim at scaling functional connectivity to a just balance between the atrophic and hypertrophic systems. However, the exact factors that can help reach this objective are still unclear. Similarities between the effects of chronic stress and some neuropathological mechanisms underlying AD dementia support the idea that common components deserve prime attention as therapeutic targets.

How can we interpret the relationship between liquid-liquid phase separation and amyotrophic lateral sclerosis

One of the critical definitions of neurodegenerative diseases is the formation of insoluble intracellular inclusion body. These inclusions are found in various neurodegenerative diseases such as Alzheimers disease, amyotrophic lateral sclerosis (ALS), Huntingtons disease, Parkinsons disease, and frontotemporal dementia (FTD). Each inclusion body contains disease-specific proteins and is also resistant to common detergent treatments. These aggregates are generally ubiquitinated and thus recognized as misfolded by the organism. They are observed in residual neurons at the affected sites in each disease, suggesting a contribution to disease pathogenesis. The molecular mechanisms for the formation of these inclusion bodies remain unclear. Some proteins, such as superoxide dismutase 1 (SOD1) mutant that causes familial ALS, are highly aggregative due to altered folding caused by point mutations. Still, the aggregates observed in neurodegenerative diseases contain wild-type proteins. In recent years, it has been reported that the proteins responsible for neurodegenerative diseases undergo liquid-liquid phase separation (LLPS). In particular, the ALSFTD causative proteins such as TAR DNA-binding protein 43 kDa (TDP-43) and fused-in-sarcoma (FUS) undergo LLPS. LLPS increases the local concentration of these proteins, and these proteins eventually change their phase from liquid to solid (liquid-solid phase transition) due to abnormal folding during repetitive separation cycles into two phases and recovery to one phase. In addition to the inclusion body formation, sequestration of essential proteins into the LLPS droplets or changes in the LLPS status can directly impair neural functions and cause diseases. In this review, we will discuss the relationship between the LLPS observed in ALS causative proteins and the pathogenesis of the disease and outline potential therapeutic approaches.

Aducanumab for the treatment of Alzheimers disease a systematic review.

Aducanumab is a novel disease-modifying anti-amyloid-beta (Aβ) human monoclonal antibody specifically targeted to the pathophysiology of Alzheimers disease (AD). It was granted for treating AD in June 2021 by the United States Food and Drug Administration. We systematically analyzed available trials to evaluate the efficacy and safety of aducanumab treating AD. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. We conducted an extensive literature search using the electronic databases MEDLINE through PubMed, EMBASE, Cochrane, Web of Science, and Scopus for suitable studies on aducanumab. We considered human clinical trials of aducanumab, assessing its efficacy and adverse effects in treating AD, excluding any experimental animal studies. We included three randomised controlled trials. Studies reported that aducanumab reduced brain amyloid-beta plaques in a time- and dose-dependent manner (dose-response, P < 0.05) and a slowed decline in cognition (22% reduction) in the high-dose treated group, difference of -0.39 versus placebo in Clinical Dementia Rating Scale Sum Boxes (95% CI, -0.69 to -0.09 P 0.012) along with a reduced amyloid positron emission tomography standard uptake value ratio score (P < 0.001) and plasma p181-tau (phosphorylated tau) level. Amyloid-related imaging abnormality was reported as a serious adverse event and was profound in high-dose treated group (4251029 in 10 mgkg). Aducanumab has been reported to affect two main pathophysiologic hallmarks (Aβ and tau) of AD. We suggest future studies addressing aducanumabs efficacy and safety to confirm that the benefit of this drug outweighs the risk.

Comparison Between

To determine the imaging characteristics and cutoff value of We prospectively enrolled 35 patients with cognitive impairment who underwent FBB-PET, FC119S-PET, and brain magnetic resonance imaging. We measured global and vertex-wise standardized uptake value ratios (SUVRs) using a surface-based method with the cerebellar gray matter as reference. Optimal global FC119S SUVR cutoffs were determined using receiver operating characteristic curves for β-amyloid positivity based on the global FBB SUVR of 1.478 and presence of AD, respectively. We evaluated the global and vertex-wise SUVR correlations between the two tracers. In addition, we performed correlation analysis for global or vertex-wise SUVR of each tracer with the vertex-wise cortical thicknesses. The optimal global FC119S SUVR cutoff value was 1.385 both for detecting β-amyloid positivity and for detecting AD. Based on the global SUVR cutoff value of each tracer, 32 (91.4%) patients had concordant β-amyloid positivity. The SUVRs of FC119S and FBB had strong global ( Quantitative FC119S-PET analysis provided reliable information for detecting β-amyloid deposition and the presence of AD.

Essential oil of Acorus tatarinowii Schott inhibits neuroinflammation by suppressing NLRP3 inflammasome activation in 3 × Tg-AD transgenic mice.

Shi chang pu (Acorus tatarinowii Schott) is a herbal used in the treatment of Alzheimers disease (AD) in China. The essential oil of Shi chang pu (SCP-oil) is the main active component. However, its effects on the neuroinflammation of AD have not been well studied. Neuroinflammation mediated by the NLRP3 inflammasome plays a crucial role in AD. This study was designed to evaluate the effect of SCP-oil on cognitive impairment of App Thirty-two 3 × Tg-AD mice at 12 months and 8 wild-type B6 mice were used for this experiment. The 3 × Tg-AD mice were administered with SCP-oil or donepezil hydrochloride for 8 weeks. Morris water maze test and step-down test were used to evaluate the cognitive ability of mice. The pathological changes, neuroinflammation, and the NLRP3 inflammasome related-protein of AD mice were detected by histomorphological examination, TUNEL staining, immunofluorescence, immunohistochemistry, qRT-PCR, Elisa, and western blot assays. SCP-oil treatment attenuated cognitive dysfunction of 3 × Tg-AD mice. Moreover, SCP-oil also ameliorated characteristics pathological of AD, such as pathological changes damage, deposition of Aβ, phosphorylation of Tau, and neuronal loss. Additionally, SCP-oil treatment alleviated the neuroinflammation and inhibited phosphorylation of IKKβ, NF-κB, and NLRP3 inflammasome related-protein NLRP3, ASC, Caspase-1, cleaved-Caspase-1, and GSDMD-N in the hippocampus of 3 × Tg-AD mice. Overall, SCP-oil contributed to neuroprotection in 3 × Tg-AD mice by reduced activation of NLRP3 inflammasome by inhibiting the NF-κB signaling pathway.

Impact of a short-duration experiential learning activity on DPT students attitudes toward patients living with a dementia.

Healthcare practitioners (HCP) have expressed inadequate preparation in providing care to patients living with a dementia. Research suggests experiential learning activities (ELAs) can improve HCP knowledge and comfort toward this population. The purpose of this study was to evaluate the impact of a short-duration (2-hour) dementia ELA on Doctor of Physical Therapy (DPT) students knowledge and comfort toward individuals living with a dementia. Participants included a sample of first-year DPT students (n82). In this pre-experimental, single-site, longitudinal study, students participated in an ELA at a memory care facility. They completed a dementia knowledge and comfort survey pre-(T1) and post-ELA(T2), as well as prior to their first clinical experience (nine months post-ELA T3). Pre- and post-survey analysis demonstrated significant improvements between T1 to T2 and T1 to T3 with overall effect sizes ranging from very large (d1.256) to huge (d1.520). There were no significant differences between T2 to T3 analysis. Students demonstrated positive improvements in attitudes toward individuals living with a dementia following this ELA. Improvements were maintained over time. An ELA as short as two hours may improve person-centered care for patients living with a dementia. These types of activities should be considered for inclusion in DPT curricula.

Meta-analysis and systematic review of peripheral platelet-associated biomarkers to explore the pathophysiology of alzheimers disease.

Platelets are the primary peripheral reserve of amyloid precursor protein (APP), providing more than 90% of blood amyloid-beta (Aβ). Some oxidative stress markers and neurotransmitter markers were also differentially expressed in the peripheral platelets of AD. Therefore, the present study explored the differences in platelet-associated biomarkers between AD and healthy controls using meta-analysis and systematic review to reveal the value of platelet in the pathogenesis and development of AD. We searched all the related studies that probed into the platelets in AD based on PubMed, Embase, and web of science databases from the establishment to November 04, 2021. Eighty-eight studies were included in the meta-analysis, and the platelets data of 702 AD and 710 controls were analyzed. The results of standardized mean difference (SMD) showed that platelets in AD had lower levels of APP ratio (SMD -1.89 p < 0.05), ADAM10 (SMD -1.16 p < 0.05), Na -K -ATPase (SMD -7.23 p < 0.05), but higher levels of HMWLMW tau (SMD 0.92 p < 0.05), adenosine A The results of the present meta-analysis and systematic review demonstrated that the alterations of APP metabolic enzymes, oxidative stress markers, and neurotransmitter factors in platelets were similar to their changes in the central nervous system of AD, suggesting that platelet could be a good source of peripheral biomarkers and may play an important role in the pathophysiological development of AD.

A Jacobnsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death.

Jacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-β and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimers disease pathology and the absence of Jacob protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. nsmf is the gene that encodes for the Jacob protein. Here we show that organotypic hippocampal slices from wild-type and nsmf

The Psychological Science Accelerators COVID-19 rapid-response dataset.

In response to the COVID-19 pandemic, the Psychological Science Accelerator coordinated three large-scale psychological studies to examine the effects of loss-gain framing, cognitive reappraisals, and autonomy framing manipulations on behavioral intentions and affective measures. The data collected (April to October 2020) included specific measures for each experimental study, a general questionnaire examining health prevention behaviors and COVID-19 experience, geographical and cultural context characterization, and demographic information for each participant. Each participant started the study with the same general questions and then was randomized to complete either one longer experiment or two shorter experiments. Data were provided by 73,223 participants with varying completion rates. Participants completed the survey from 111 geopolitical regions in 44 unique languagesdialects. The anonymized dataset described here is provided in both raw and processed formats to facilitate re-use and further analyses. The dataset offers secondary analytic opportunities to explore coping, framing, and self-determination across a diverse, global sample obtained at the onset of the COVID-19 pandemic, which can be merged with other time-sampled or geographic data.

Could Alzheimers disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism

An important aspect of survival is to assure enough food, water, and oxygen. Here, we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose, which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in a resting human amounts to 20% of the overall energy demand, is only beginning to be understood. Here, we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimers disease and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged in multiple ways, including diets high in sugar, high glycemic carbohydrates, and salt. In summary, we propose that Alzheimers disease may be the consequence of a maladaptation to an evolutionary-based survival pathway and what had served to enhance survival acutely becomes injurious when engaged for extensive periods. Although more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimers disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine whether there is potential benefit in the prevention, management, or treatment of this disease.

Empirical Dietary Inflammatory Pattern Scores Are Not Associated with Worse Cognitive Performance in the Nurses Health Study.

Low-grade chronic inflammation associated with unhealthy diets may lead to cognitive aging. We evaluated whether higher long-term adherence to an empirical dietary inflammatory pattern (EDIP) was associated with lower cognitive function after age 70 y in the Nurses Health Study. A total of 16,058 older (mean ± SD age 74 ± 2 y) highly educated (≥ bachelor degree) White women completed up to 5 validated 116-item food-frequency questionnaires. An EDIP score, previously derived with the use of reduced rank regression to predict circulating inflammatory markers (i.e., C-reactive protein, TNF-α receptor 2, and IL-6), was computed based on 9 anti-inflammatory and 9 proinflammatory components. A long-term EDIP score was calculated by averaging across 5 exams. The EDIP score was categorized into quintiles, taking the first (anti-inflammatory) quintile as the reference category. Cognitive testing was performed through telephone interviews over 4 follow-up exams (1995-2008). A composite global cognition score, a composite verbal memory score, and the Telephone Interview for Cognitive Status (TICS) were calculated and averaged across the 4 exams (6 y of follow-up). Multivariable linear regressions were used to examine longitudinal relations under study. Higher long-term EDIP scores (i.e., more proinflammatory) were significantly associated with worse performance on global cognitive function (P-trend 0.018) and TICS (P-trend 0.004) after adjustment for demographic and lifestyle factors. The associations became nonsignificant after additional adjustments for disease (related) risk factors for dementia. No association was observed between the EDIP score and verbal memory. We observed no relation between long-term EDIP scores and averaged global cognitive function and verbal memory among older women. Our findings suggest no relation between long-term adherence to a proinflammatory diet and cognitive function in a large population of mostly White and generally highly educated older women. Future studies are encouraged to investigate the relation between inflammatory diets and cognitive function in other racesethnicities and men, and over a longer follow-up period.

Unsaturated Fatty Acids in Mental Disorders An Umbrella Review of Meta-Analyses.

Unsaturated fatty acids might be involved in the prevention of and improvement in mental disorders, but the evidence on these associations has not been comprehensively assessed. This umbrella review aimed to appraise the credibility of published evidence evaluating the associations between unsaturated fatty acids and mental disorders. In this umbrella review, systematic reviews and meta-analyses of studies comparing unsaturated fatty acids (including supplementation, dietary intake, and blood concentrations) in participants with mental disorders with healthy individuals were included. We reanalyzed summary estimates, between-study heterogeneity, predictive intervals, publication bias, small-study effects, and excess significance bias for each meta-analysis. Ninety-five meta-analyses from 29 systematic reviews were included, encompassing 43 studies on supplementation interventions, 32 studies on dietary factors, and 20 studies on blood biomarkers. Suggestive evidence was only observed for dietary intake, in which higher intake of fish was associated with reduced risk of depression (RR 0.78 95% CI 0.69, 0.89) and Alzheimer disease (RR 0.74 95% CI 0.63, 0.87), and higher intake of total PUFAs might be associated with a lower risk of mild cognitive impairment (RR 0.71 95% CI 0.61, 0.84). Evidence showed that PUFA supplementation was favorable but had weak credibility in anxiety, depression, attention-deficithyperactivity disorder (ADHD), autism spectrum disorder (ASD), dementia, mild cognitive impairment, Huntingtons disease, and schizophrenia (P-random effects <0.001-0.040). There was also weak evidence on the effect of decreased circulating n-3 (ɷ-3) PUFAs among patients on risk of ADHD, ASD, bipolar disorder, and schizophrenia (P-random effects <10

Four-dimensional microED of conformational dynamics in protein microcrystals on the femto-to-microsecond timescales.

As structural determination of protein complexes approaches atomic resolution, there is an increasing focus on conformational dynamics. Here we conceptualize the combination of two techniques which have become established in recent years microcrystal electron diffraction and ultrafast electron microscopy. We show that the extremely low dose of pulsed photoemission still enables microED due to the strength of the electron bunching from diffraction of the protein crystals. Indeed, ultrafast electron diffraction experiments on protein crystals have already been demonstrated to be effective in measuring intermolecular forces in protein microcrystals. We discuss difficulties that may arise in the acquisition and processing of data and the overall feasibility of the experiment, paying specific attention to dose and signal-to-noise ratio. In doing so, we outline a detailed workflow that may be effective in minimizing the dose on the specimen. A series of model systems that would be good candidates for initial experiments is provided.

Air pollution and plasma amyloid beta in a cohort of older adults Evidence from the Ginkgo Evaluation of Memory study.

Air pollution has been linked to Alzheimers disease and related dementias (ADRD), but the mechanisms connecting air pollution to ADRD have not been firmly established. Air pollution may cause oxidative stress and neuroinflammation and contribute to the deposition of amyloid beta (Aβ) in the brain. We examined the association between fine particulate matter<2.5 μm in diameter (PM

Recovery of neurosurgical high-frequency electroporation injury in the canine brain can be accelerated by 7,8-dihydroxyflavone.

Although traumatic brain injury (TBI) occurs in a very short time, the biological consequence of a TBI, such as Alzheimers disease, may last a lifetime. To date, effective interventions are not available to improve recovery from a TBI. Herein we aimed to ascertain whether recovery of neurosurgical high-frequency irreversible electroporation (HFIRE) injury in brain tissues can be accelerated by 7,8-dihydroxyflavone (7,8-DHF). The HFIRE injury was induced in the right parietal cortex of 8 adult healthy and neurologically intact male dogs. Two weeks before HFIRE injury, each dog was administered orally with or without 7,8-DHF (30 mgkg) once daily for consecutive 2 weeks (n 4 for each group). The values of blood-brain barrier (BBB) disruption, brain edema, and cerebral infarction volumes were measured. The concentrations of beta-amyloid, interleukin-1β, interleukin-6 and tumor necrosis factor-α in the cerebrospinal fluid were measured biochemically. The BBB disruption, brain edema, infarction volumes, and maximal cross-section area caused by HFIRE injury in canine brain were significantly attenuated by 7,8-DHF therapy (P < 0.0001). Additionally, 7,8-DHF significantly reduced the HFIRE-induced cerebral overproduction of beta-amyloid and proinflammatory cytokines in the cerebrospinal fluid (P < 0.0001) in dogs with HFIRE. Recovery of neurosurgical HFIRE injury in canine brain tissues can be accelerated by 7,8-DHT via ameliorating BBB disruption as well as cerebral overproduction of both beta-amyloid and proinflammatory cytokines.

A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimers disease β-site amyloid precursor protein cleaving enzyme 1 (BACE-1).

The clinically important anticoagulant heparin, a member of the glycosaminoglycan family of carbohydrates that is extracted predominantly from porcine and bovine tissue sources, has previously been shown to inhibit the β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key drug target in Alzheimers Disease. In addition, heparin has been shown to exert favourable bioactivities through a number of pathophysiological pathways involved in the disease processes of Alzheimers Disease including inflammation, oxidative stress, tau phosphorylation and amyloid peptide generation. Despite the multi-target potential of heparin as a therapeutic option for Alzheimers disease, the repurposing of this medically important biomolecule has to-date been precluded by its high anticoagulant potential. An alternative source to mammalian-derived glycosaminoglycans are those extracted from marine environments and these have been shown to display an expanded repertoire of sequence-space and heterogeneity compared to their mammalian counterparts. Furthermore, many marine-derived glycosaminoglycans appear to retain favourable bioactivities, whilst lacking the high anticoagulant potential of their mammalian counterparts. Here we describe a sulphated, marine-derived glycosaminoglycan extract from the Atlantic Sea Scallop, Placopecten magellanicus that displays high inhibitory potential against BACE-1 (IC

Retinal pathological features and proteome signatures of Alzheimers disease.

Alzheimers disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ

Validation study of the Persian version of behavioral pathology in Alzheimers Disease Rating scale (BEHAVE-AD) and the empirical BHAVE-AD (E-BEHAVE-AD).

Behavioral and psychological symptoms of dementia (BPSD) are observed in more than 90% of patients with Alzheimers disease (AD). BPSDs are remediable if detected early and managed appropriately. Behavioral Pathology in Alzheimers disease Rating Scale (BEHAVE-AD) and Empirical BEHAVE-AD (E-BEHAVE-AD) were designed to identify BPSD. The aim of this study is to validate and prepare BEHAVE-AD and E-BEHAVE-AD in Persian language for clinical and research applications. 120 patients were selected through a combination of intentional and convenience sampling. All participants should fulfill the NINCDS-ADRDA Work Group criteria for a clinical diagnosis of Alzheimers disease. Functional Assessment Staging Tool (FAST) was used to determine the rate of AD progression. All patients were evaluated using the BEHAVE-AD and E-BEHAVE-AD questionnaires, as well as the Persian version of the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Mini-Mental State Examination (MMSE). The Content Validity Index (CVI) is determined based on the compatibility of the Persian and the original version of the two scales according to the opinion of expert panels. Correlation of MMSE with BEHAVE-AD and E-BEHAVE-AD as well as the BPSD pattern on AD progression continuum by FAST were considered as indices of construct validity. Concurrent validity was estimated by correlating NPI-Q scores with BEHAVE-AD and E-BEHAVE-AD scores. For both scales, interrater reliability was extracted as a reliability index. Pearson correlation coefficients for the BEHAVE-AD scale were as follows with NPI-Q ( The Persian version of BEHAVE-AD and E-BEHAVE-AD is valid and reliable for the assessment of BPSD in patients with AD.

Convolution Neural Networks and Self-Attention Learners for Alzheimer Dementia Diagnosis from Brain MRI.

Alzheimers disease (AD) is the most common form of dementia. Computer-aided diagnosis (CAD) can help in the early detection of associated cognitive impairment. The aim of this work is to improve the automatic detection of dementia in MRI brain data. For this purpose, we used an established pipeline that includes the registration, slicing, and classification steps. The contribution of this research was to investigate for the first time, to our knowledge, three current and promising deep convolutional models (ResNet, DenseNet, and EfficientNet) and two transformer-based architectures (MAE and DeiT) for mapping input images to clinical diagnosis. To allow a fair comparison, the experiments were performed on two publicly available datasets (ADNI and OASIS) using multiple benchmarks obtained by changing the number of slices per subject extracted from the available 3D voxels. The experiments showed that very deep ResNet and DenseNet models performed better than the shallow ResNet and VGG versions tested in the literature. It was also found that transformer architectures, and DeiT in particular, produced the best classification results and were more robust to the noise added by increasing the number of slices. A significant improvement in accuracy (up to 7%) was achieved compared to the leading state-of-the-art approaches, paving the way for the use of CAD approaches in real-world applications.

Investigation of