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Clinical Observation of Computer Vision Technology Combined with Music Therapy in the Treatment of Alzheimers Disease.

With the worlds population aging, Alzheimers disease has attracted more and more attention as a common elderly disease. The clinical manifestations of cognitive function decline in Alzheimers disease are mainly memory decline, which will seriously damage the patients sense of self-worth. The purpose is to use the method of song recall to conduct individual music therapy intervention for Alzheimers disease patients, to help Alzheimers disease patients activate autobiographical memory, trigger positive emotions, improve behavioral symptoms, and delay the development of the disease. This paper proposes to combine computer vision technology with music therapy to obtain relevant data before and after intervention through the literature method, measurement method, case study method and experimental method. It helps AD patients to improve and slow down the forgetting and confusion of autobiographical memory, thereby enhancing the mood and cognition of AD patients. It observes the changes of AD patients before and after intervention by song recall and provides new ideas and practical basis for the application of music therapy in the field of Alzheimers disease research. The experimental results showed that the subjects autobiographical memory test (AMT) after 16 sessions of music therapy, from 12 points before the test to 14 points after the test. The scores were significantly positively correlated, and the improvement of autobiographical memory could improve the patients orientation and memory.

A Validation Study of the Hong Kong Brief Cognitive Test for Screening Patients with Mild Cognitive Impairment and Alzheimers Disease.

The Hong Kong Brief Cognitive Test (HKBC), a brief instrument designed to screen for cognitive impairment in older adults, has been validated in Cantonese-speaking populations and has shown better performance than the Mini-Mental State Examination (MMSE) in detecting both mild and major neurocognitive disorder (NCD). This study aimed to validate the HKBC for detecting patients with amnestic mild cognitive impairment (aMCI) and Alzheimers disease (AD) in a Mandarin-speaking Chinese population. Two hundred forty-eight patients with aMCI, 67 patients with mild AD and 306 healthy controls (HCs) were recruited for this study and completed both the HKBC and the MMSE. The performance of the HKBC and MMSE in distinguishing patients with aMCI from HCs and distinguishing patients with AD from patients with aMCI was compared in the whole population and in age- and education-stratified subgroups. The optimal HKBC cutoff score for distinguishing patients with aMCI from HCs was 23, and the optimal cutoff score for distinguishing patients with AD from patients with aMCI was 17. The HKBC significantly outperformed the MMSE at differentiating patients with aMCI from HCs in the whole population (z 12.38, p < 0.01) and all subgroups stratified by age or education. Regarding the discrimination of patients with AD from patients with aMCI, the HKBC showed better performance than the MMSE in the oldest subgroup (z 2.18, p 0.03). The HKBC is a sensitive and specific screening tool for detecting aMCI and AD in the Chinese population across age groups and educational levels.

The Use of Digital Technology to Assess Cognitive Function in Tunisian Adults.

There has been increasing evidence and support for the use of digital technology in the cognitive health field. Despite the growing use of innovative digital technology to assess cognitive function, such technology remains scarce in Arabic countries, particularly in Tunisia. To investigate the effectiveness of a digitally delivered cognitive assessment battery in differentiating varying degrees of cognitive function in older Tunisian adults. One hundred fifty-five Tunisian older adults (age 62.24±7.52 years) were assigned to one of four groups healthy controls (HC), at-risk (AR), mild cognitive impairment (MCI), and Alzheimers disease (AD). Participants completed a translated version of the Neurotrack digital cognitive battery. The AD group performed significantly lower on the associative learning (p 0.01) and associative memory assessments (p 0.002), than the HC and AR groups. The AD group also performed worse on the inhibition measure (p 0.008) than the HC, AR, and MCI groups. For recognition memory, the was a significant difference between all four groups (p < 0.0005), with AD having the lowest scores followed by the MCI, AR, and HC groups, respectively. There were no significant differences observed on attention, executive function and processing speed performance between the four groups (p > 0.05). The use of digital technology appears to be a viable solution to current cognitive assessment challenges for assessing cognitive function in a Tunisian population. These findings provide further support for the use of digital technology in cognitive assessment, particularly in understudied populations.

Regulation of the Human IL-10RB Gene Expression by Sp8 and Sp9.

Interleukin-10 (IL-10) is a classic anti-inflammatory cytokine that exerts its effects via the receptor complexes IL-10RA and IL-10RB. Loss of IL-10RB results in many diseases. Moreover, IL-10RB is closely associated with neuronal survival and synaptic formation. However, the regulation of IL-10RB gene expression remains elusive. To investigate whether the expression of IL-10RB gene is increased in brain of Alzheimers disease (AD) and its transcriptional regulation. We examined the gene expression of AD patient brain from public database and detected the protein expression of AD model mouse brain by western blot. We constructed a variety of reporter gene plasmids with different lengths or mutation sites, tested the promoter activity and defined the functional region of the promoter with the luciferase reporter assay. The protein-DNA binding between transcription factors and the promoter was analyzed using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). We found that the IL-10RB is elevated in the brain of AD patient and AD model mice. The minimal promoter of the IL-10RB gene is located in the -90 to 51 bp region (relative to the transcriptional start site) and is sufficient for high-level expression of the IL-10RB gene. Transcription factors Sp8 and Sp9 bind to the IL-10RB promoter in vitro. The overexpression or knockdown of Sp8 and Sp9 affected the IL-10RB promoter activity and its gene expression. Our study functionally characterized the promoter of the IL-10RB gene and demonstrated that Sp8 and Sp9 regulated its expression.

Evoked Cortical Depolarizations Before and After the Amyloid Plaque Accumulation Voltage Imaging Study.

In Alzheimers disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline. Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings. Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswePS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes). Expression of GEVI did not disrupt AD model formation of amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 23. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting hyperexcitability prior to the formation of plaques. Our results indicate bidirectional alterations in cortical physiology in AD model mice occurring both prior (P40-80), and after (P150-200) the amyloid deposition.

The Effects of Normal Aging, Subjective Cognitive Decline, Mild Cognitive Impairment, or Alzheimers Disease on Visual Search.

Alzheimers disease (AD) has been confirmed as an influencing factor of visual impairment, but potential concomitant effects on visual and cognitive performance are not well understood. To provide a new method for early screening of Alzheimers disease and further explore the theoretical mechanism of the decline of whole visual and cognitive performance in AD. We studied 60 individuals without dementia as normal control (NC), 74 individuals with subjective cognitive decline (SCD), 60 individuals with amnesia mild cognitive impairment (aMCI), and 75 patients with AD on a battery of tests designed to measure multiple aspects of basic and higher-order visual perception and cognition. All subjects performed on same visual and cognitive test batteries. The results showed both of four groups, with the stimulus-presentation time being longer, the visual-search performance improved, and both the eye interest-area first fixation duration and the interest-area-fixation count increased. Particularly under the noise-masking condition, the AD group performed the worst at stimulus-presentation times between 300 and 900 ms. The aMCI group, but not the SCD group, performed worse than the NC group at the stimulus-presentation time of either 300 or 500 ms. The interest-area-fixation count was higher in all the patient groups than that in the NC group, and distinguishable between participants with AD and those with SCD or aMCI. The visual-search performance combined with eye-movement tracking under the noise-masking condition can be used for distinguishing AD from normal aging, SCD, and aMCI.

An Elicitation Study to Understand Black, Hispanic, and Male Older Adults Willingness to Participate in Alzheimers Disease-Focused Research Registries.

There is a lack of racial, ethnic, and sex diversity in recruitment research registries and Alzheimers disease (AD) research studies and trials. Theory-based recruitment messages may provide an opportunity to increase study participant diversity in AD research studies and trials. To identify behavioral, normative, and control beliefs that are associated with joining an AD-focused recruitment registry among historically underrepresented groups. Using a Reasoned Action Approach, we conducted 60 semi-structured phone interviews in 2020 among White, Black, and Hispanic adults ages 49-79 years in Philadelphia, PA. Underlying beliefs were elicited for the target behavior of signing up to be on a registry for brain health research studies in the next month. Percentages based on counts are reported for the overall sample and by race and ethnicity and sex. Participants were most concerned that if they were to sign up for a registry, they would be asked to participate in experimental studies. Advancing science to help others was a commonly reported positive belief about signing up. Participants children and friendsneighbors were important from a normative perspective. Barriers to enrollment focused on logistical concerns and inconvenient sign-up processes, including using a computer. Results show generally few racial and ethnic or sex group differences. The elicited beliefs from underrepresented groups offer a basis for understanding the behavior of signing up for research registries. However, there were few differences between the groups. Implications for outreach and recruitment are discussed.

Polygenic Scores of Alzheimers Disease Risk Genes Add Only Modestly to APOE in Explaining Variation in Amyloid PET Burden.

Brain accumulation of amyloid-β is a hallmark event in Alzheimers disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimers Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p 1.51×10-50) and ADNI (p 3.21×10-64). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA 2.1%, ADNI 4.4%) to explaining variation in amyloid PET levels. Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

Combinational Drug Repurposing from Genetic Networks Applied to Alzheimers Disease.

Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimers disease.

Upregulated Blood miR-150-5p in Alzheimers Disease Dementia Is Associated with Cognition, Cerebrospinal Fluid Amyloid-β, and Cerebral Atrophy.

There is an urgent need for noninvasive, cost-effective biomarkers for Alzheimers disease (AD), such as blood-based biomarkers. They will not only support the clinical diagnosis of dementia but also allow for timely pharmacological and nonpharmacological interventions and evaluations. To identify and validate a novel blood-based microRNA biomarker for dementia of the Alzheimers type (DAT). We conducted microRNA sequencing using peripheral blood mononuclear cells isolated from a discovery cohort and validated the identified miRNAs in an independent cohort and AD postmortem tissues. miRNA correlations with AD pathology and AD clinical-radiological imaging were conducted. We also performed bioinformatics and cell-based assay to identify miRNA target genes. We found that miR-150-5p expression was significantly upregulated in DAT compared to mild cognitive impairment and healthy subjects. Upregulation of miR-150-5p was observed in AD hippocampus. We further found that higher miR-150-5p levels were correlated with the clinical measures of DAT, including lower global cognitive scores, lower CSF Aβ42, and higher CSF total tau. Interestingly, we observed that higher miR-150-5p levels were associated with MRI brain volumes within the default mode and executive control networks, two key networks implicated in AD. Furthermore, pathway analysis identified the targets of miR-150-5p to be enriched in the Wnt signaling pathway, including programmed cell death 4 (PDCD4). We found that PDCD4 was downregulated in DAT blood and was downregulated by miR-150-5p at both the transcriptional and protein levelsConclusionOur findings demonstrated that miR-150-5p is a promising clinical blood-based biomarker for DAT.

Assessment of the Causal Effect of IgG N-Glycosylation Level on Risk of Dementia A 2-Sample Mendelian Randomization Study.

Previous prospective studies highlighted aberrant immunoglobulin G (IgG) N-glycosylation as a risk factor for dementia such as Alzheimers disease (AD) and vascular dementia (VaD). It is unclear whether this association is causal or explained by confounding or reverse causation. The aim is to examine the association of genetically predicted IgG N-glycosylation with dementia using 2-sample Mendelian randomization (MR). Independent genetic variants for IgG N-glycosylation traits were selected as instrument variables from published genome-wide association studies (GWAS) among individuals of European ancestry. We extracted their corresponding summary statistics from large-scale clinically diagnosed AD GWAS dataset and FinnGen biobank VaD GWAS dataset. The inverse variance weighted (IVW) was performed to calculate the effect estimates. Meanwhile, multiple sensitivity analyses were used to assess horizontal pleiotropy and outliers. There were no associations of genetically predicted IgG N-glycosylation traits with the risk of AD and VaD using the IVW method (all Bonferroni corrected p > 0.0013). These estimates of four additional sensitivity analyses methods were consistent with the IVW estimates in terms of direction and magnitude. Additionally, the MR-PRESSO global test and the intercept of MR-Egger regression indicated no evidence of horizontal pleiotropy. Meanwhile, the heterogeneity test showed no significant heterogeneity using the Cochran Q statistic. The leave-one-out sensitivity analyses also did not detect any significant change. Our MR study did not support evidence for the hypothesis that IgG N-glycosylation level may be causally associated with the risk of dementia.

Organized Registration for the Assessment of Dementia by the Nationwide General Consortium Toward Effective Treatment (ORANGE) Registry Current Status and Perspectives of Mild Cognitive Impairment.

With increasingly aging societies, a comprehensive strategy for dementia research is important. The Organized Registration for the Assessment of dementia by the Nationwide General consortium toward Effective treatment (ORANGE) Registry is the first longitudinal multicenter prospective trial-ready cohort in Japan. To establish a large cohort for use in clinical trials and research in Japan. This registry, based on communities, hospitals, and nursing homes, covers three dementia stages (preclinical, mild cognitive impairment MCI, and advanced dementia), and includes more than 30 hospitals. We analyzed enrollment and 1-year follow-up data for disease progression. There were 1450 registered patients (649 men, 801 women mean age, 77.92±6.70 years mean Mini-Mental State Examination MMSE score, 25.19±2.76). The conversion rates from MCI to dementia and MCI to normal were 14.3% and 1.1%, respectively. High Clinical Dementia Rating score (odds ratio OR 11.085, 95% confidence interval CI1.619-75.913, p 0.014), low MMSE score (OR 0.835, 95% CI 0.761-0.917, p < 0.001), high Geriatric Depression Scale score (OR 1.093, 95% CI 1.005-1.189, p 0.038), and low body mass index (OR 0.895, 95% CI 0.829-0.967, p 0.005) at enrollment were significant factors for conversion. The ORANGE MCI Registry is an established registry that facilitates creation of trial-ready cohorts to accelerate promotion of clinical trials with low reversion rates as it originates from a hospital. One-year follow-up analysis suggested assessing various factors for conversion risk. Further analyses will be possible in future with registry expansion. We will continue to refine this registry, including how it can be used more efficiently.

Precision Medicine Approach to Alzheimers Disease Successful Pilot Project.

Effective therapeutics for Alzheimers disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. To determine whether a precision medicine approach to Alzheimers disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t 0, 3, 6, and 9 months. All outcome measures revealed improvement statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimers Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimers Disease.

In Alzheimers disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohens kappa values of 0.89 and 0.86 respectively). Tracer retention in a hook-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.

A Comparison of Operational Definitions for Mild Cognitive Impairment.

Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking. Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia, or a biomarker profile indicative for Alzheimers disease (AD). Memory clinic patients without dementia (N 558 mean age 66 up to 3 years of follow-up n 360 with baseline CSF biomarkers) were included in an observational study using most liberal criteria of cognitive impairment. Four operational definitions of MCI were retrospectively applied 1) amnestic MCI (CERAD word list delayed recall), 2) CERAD total score, 3) comprehensive criteria and 4) base rate corrected CERAD. We compared their accuracy in predicting incident all-cause dementia or AD dementia within three years, or a concurrent CSF Aβ42tau-ratio indicative of AD. The four definitions overlapped considerably, classified 35-58% of the original sample as impaired and were associated with markedly increased PPVs regarding incident all-cause dementia (39-46% versus 26% of the original sample), AD dementia and AD biomarker positivity. The base rate corrected MCI definition had the highest prognostic accuracy. he operational criteria examined seem suitable to specify MCI in memory clinic settings, as they identify subjects at high risk of clinical progression. Depending on the neuropsychological battery in use, one or several of these criteria could help to calibrate the clinical judgment of test results, reduce false-positive decisions, and define risk-enriched groups for clinical trials.

The recognition and management of neuropsychiatric symptoms in early Alzheimers disease a qualitative study among Dutch memory clinic physicians.

Timely recognition and treatment of neuropsychiatric symptoms (NPS) in Alzheimers disease (AD) dementia may improve quality of life, reduce caregiver burden, and delay disease progression. However, management of NPS in early AD dementia remains challenging. To date, little is known about the specific challenges for memory clinic-based physicians. The aims of this qualitative study were to obtain insights regarding the recognition and treatment of NPS in AD dementia in the memory clinic, to identify challenges experienced by physicians while managing NPS, and to examine the attitudes of memory clinic physicians on the role of the memory clinic in the care for NPS in early AD dementia. Semi-structured interviews were conducted with 13 physicians working at a memory clinic in the Netherlands (n 7 neurologist, n 6 geriatrician, 46% female). The data were analyzed by two independent researchers using thematic analysis. We observed large variation among Dutch memory clinic physicians regarding care practices, expertise, and attitudes on the role of the memory clinic considering NPS in AD dementia. The most prominent challenges that memory clinic physicians experienced while managing NPS included that the outpatient setting complicates the recognition and treatment of NPS, a lack of experience, knowledge, andor resources to adequately apply non-pharmacological interventions, and a lack of consensus among physicians on the role of the memory clinic in NPS recognition and management. We identified challenges that need to be addressed to improve the early recognition and adequate management of NPS in AD dementia at the memory clinic.

Cognitive and neuroimaging correlates of financial exploitation vulnerability in older adults without dementia Implications for early detection of Alzheimers disease.

Neuropathology characteristic of Alzheimers disease (AD) begins to accumulate years to decades before cognitive changes are clinically detectable on standard neuropsychological tests. This presents a challenge for early intervention efforts and has spurred research on the identification of behavioral correlates of early neuropathological changes. Recent evidence suggests that financial exploitation vulnerability (FEV) due to impaired decision making may serve as an early behavioral manifestation of AD neuropathology, thereby indicating an increased likelihood for subsequent cognitive decline. An understanding of the underlying mechanisms of FEV is therefore warranted for the identification of individuals at risk for cognitive decline due to AD, and for empowering and protecting older adults vulnerable to financial exploitation. In the current review, we first highlight the devastating consequences of financial exploitation of older adults. We then summarize research on the cognitive, neuroimaging, and neuropathological correlates of FEV in older adults without dementia and propose a theoretical model in which early accumulation of AD pathology manifests as FEV. We conclude with clinical implications and directions for future research.

DMTHB ameliorates memory impairment in Alzheimers disease mice through regulation of neuroinflammation.

Alzheimers disease (AD) is one of the most prevalent neurodegenerative diseases. Growing evidence suggested that AD is associated with neuroinflammation, characterized with the chronic activation of microglial cells and astrocytes along with the subsequent excessive generation of the proinflammatory molecules. This study aimed to investigate the effect and molecular mechanism of Demethylenetetrahydroberberine (DMTHB) on Alzheimers disease (AD). AD mice model were made by intracranial injection of Aβ Our results showed that the cognition of AD mice was significantly improved by DMTHB administration. DMTHB inhibited the activation of the microglia and significantly reduced the expression of Iba-1 in the brains of AD mice. In addition, DMTHB effectively suppressed the activation of NLRP3 inflammasome induced by Aβ These results indicated that DMTHB could be a potential medicine against AD through regulation of neuroinflammation.

The role of antiviral CD8

The impact of the immune system on the etiopathogenesis of neurodegenerative diseases, including Alzheimers disease, is a rapidly growing area of investigation. Evidence from human patients and animal models implicates neurotropic viral infections, and specifically the antiviral immune response of brain-infiltrating CD8

Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia.

Anesthesia induces Tau phosphorylation and cognitive impairment in young, but not adult, mice. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its toxic fragments are reported to induce neurodegeneration and neurocognitive impairment in patients with Alzheimers disease (AD). Therefore, we set out to test the hypothesis that the difference in ApoE fragments, but not the full-length ApoE, contributes to the difference in Tau phosphorylation and neurocognitive functions following sevoflurane anesthesia in young mice. Sevoflurane was administered to wild-type (WT), ApoE-knockout (ApoE-KO), ApoE3-targeted replacement (ApoE3 expresses both full-length and fragmented ApoE), and ApoE2-targeted replacement (ApoE2 only expresses full-length ApoE) mice. The mRNA and protein levels of ApoE, phosphorylated Tau (pTau), and cognitive function were tested in the mice. Sevoflurane anesthesia enhanced ApoE mRNA, total ApoE, full-length ApoE, ApoE fragments, Tau phosphorylation (AT8 and PHF1), and cognitive impairment in young mice, but not in adult mice. ApoE2, but not ApoE3 or ApoE-KO, mice showed reduced sevoflurane-induced pTau elevation and cognitive impairment. These data suggest that elevated ApoE fragments rather than full-length ApoE might be one of the underlying mechanisms of age-dependent Tau phosphorylation and cognitive impairment in young mice following sevoflurane anesthesia.

The Interaction between HLA-DRB1 and Smoking in Parkinsons Disease Revisited.

Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinsons disease (PD) yielded findings in opposite directions. To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

GRN Mutations Are Associated with Lewy Body Dementia.

Loss-of-function mutations in GRN are a cause of familial frontotemporal dementia, and common variants within the gene have been associated with an increased risk of developing Alzheimers disease and Parkinsons disease. Although TDP-43-positive inclusions are characteristic of GRN-related neurodegeneration, Lewy body copathology has also been observed in many GRN mutation carriers. The objective of this study was to assess a Lewy body dementia (LBD) case-control cohort for pathogenic variants in GRN and to test whether there is an enrichment of damaging mutations among patients with LBD. We analyzed whole-genome sequencing data generated for 2591 European-ancestry LBD cases and 4032 neurologically healthy control subjects to identify disease-causing mutations in GRN. We identified six heterozygous exonic GRN mutations in seven study participants (cases n 6 control subjects n 1). Each variant was predicted to be pathogenic or likely pathogenic. We found significant enrichment of GRN loss-of-function mutations in patients with LBD compared with control subjects (Optimized Sequence Kernel Association Test P 0.0162). Immunohistochemistry in three definite LBD cases demonstrated Lewy body pathology and TDP-43-positive neuronal inclusions. Our findings suggest that deleterious GRN mutations are a rare cause of familial LBD. © 2022 International Parkinson Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice.

Overstimulation of N-methyl-D-aspartate receptors (NMDARs) is the leading cause of brain excitotoxicity and often contributes to neurodegenerative diseases such as Alzheimers Disease (AD), the most common form of dementia. This study aimed to evaluate a new NMDA receptor antagonist (UB-ALT-EV) and memantine in 6-month-old female 5XFAD mice that were exposed orally to a chronic low-dose treatment. Behavioral and cognitive tests confirmed better cognitive performance in both treated groups. Calcium-dependent protein calpain-1 reduction was found after UB-ALT-EV treatment but not after memantine. Changes in spectrin breakdown products (SBDP) and the p25p35 ratio confirmed diminished calpain-1 activity. Amyloid β (Aβ) production and deposition was evaluated in 5XFAD mice and demonstrated a robust effect of NMDAR antagonists on reducing Aβ deposition and the number and size of Thioflavin-S positive plaques. Furthermore, glycogen synthase kinase 3β (GSK3β) active form and phosphorylated tau (AT8) levels were diminished after UB-ALT-EV treatment, revealing tau pathology improvement. Because calpain-1 is involved in autophagy activation, autophagic proteins were studied. Strikingly, results showed changes in the protein levels of unc-51-like kinase (ULK-1), beclin-1, microtubule-associated protein 1A1B-light chain 3(LC3B-II)LC3B-I ratio, and lysosomal-associated membrane protein 1 (LAMP-1) after NMDAR antagonist treatments, suggesting an accumulation of autophagolysosomes in 5XFAD mice, reversed by UB-ALT-EV. Likewise, treatment with UB-ALT-EV recovered a WT mice profile in apoptosis markers Bcl-2, Bax, and caspase-3. In conclusion, our results revealed the potential neuroprotective effect of UB-ALT-EV by attenuating NMDA-mediated apoptosis and reducing Aβ deposition and deposition jointly with the autophagy rescue to finally reduce cognitive alterations in a mice model of familial AD.

Deep learning for Alzheimers disease diagnosis A survey.

Alzheimers Disease (AD) is an irreversible neurodegenerative disease that results in a progressive decline in cognitive abilities. Since AD starts several years before the onset of the symptoms, its early detection is challenging due to subtle changes in biomarkers mainly detectable in different neuroimaging modalities. Developing computer-aided diagnostic models based on deep learning can provide excellent opportunities for the analysis of different neuroimage modalities along with other non-image biomarkers. In this survey, we perform a comparative analysis of about 100 published papers since 2019 that employ basic deep architectures such as CNN, RNN, and generative models for AD diagnosis. Moreover, about 60 papers that have applied a trending topic or architecture for AD are investigated. Explainable models, normalizing flows, graph-based deep architectures, self-supervised learning, and attention mechanisms are considered. The main challenges in this body of literature have been categorized and explained from data-related, methodology-related, and clinical adoption aspects. We conclude our paper by addressing some future perspectives and providing recommendations to conduct further studies for AD diagnosis.

The roles of GnRH in the human central nervous system.

It is widely known that GnRH plays a role in facilitating reproductive function via the HPG axis, and this was once believed to be its only function. However, over the last several decades important neuromodulatory roles of GnRH in multiple brain functions have been elucidated. Multiple GnRH isoforms and receptors have been detected outside the HPG-axis across different species. In this review, we focus on the human CNS where GnRH I and II isoforms and a functional GnRH I receptor have been isolated. We first describe the traditional understanding of GnRH within the hypothalamus and the pituitary and current clinical use of GnRH analogues. We then review the location and function of GnRH-producing neurons and receptors located outside the HPG axis. We next review the GnRH I and II neuron location and quantity and GnRH I receptor gene expression throughout the human brain, using the Allen Brain Map Atlas. This analysis demonstrates a wide expression of GnRH throughout the brain, including prominent expression in the basal forebrain and cerebellum. Lastly, we examine the potential role of GnRH in aging and inflammation and its therapeutic potential for neurodegenerative disease and spinal cord lesions.

Increased regional white matter hyperintensity volume in objectively-defined subtle cognitive decline and mild cognitive impairment.

White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimers disease (AD). Less is known about the extent and pattern of WMH in pre-MCI stages, such as among those with objectively-defined subtle cognitive decline (Obj-SCD). Five hundred and fifty-nine Alzheimers Disease Neuroimaging Initiative participants (170 cognitively unimpaired CU 83 Obj-SCD 306 MCI) free of clinical dementia or stroke completed neuropsychological testing and MRI exams. ANCOVA models compared cognitive groups on regional WMH adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 frequency. Compared with the CU group, those with Obj-SCD had greater temporal, occipital, and frontal WMH whereas those with MCI had higher WMH volume across all regions (ps < 0.01). No differences in WMH volume were observed between the Obj-SCD and MCI groups (ps > 0.05). Findings add to growing evidence of associations between Obj-SCD and imaging biomarkers, providing support for utility of these criteria to capture subtle cognitive changes that are biologically based.

Consequences of a peroxiredoxin 4 (Prdx4) deficiency on learning and memory in mice.

Peroxiredoxin 4 (Prdx4) is responsible for the oxidative folding of new proteins that are synthesized in the endoplasmic reticulum (ER). It has recently been suggested that increased ER stress is associated with neurodegenerative diseases, including Alzheimers disease. Prdx4 is widely distributed throughout the brain, and is also expressed in hippocampal neurons and oligodendrocytes, suggesting that it is associated with learning and memory. We previously established Prdx4-knockout (KO) mice but did not examine the behavioral phenotypes. In the present study, we report on the learning and memory abilities of Prdx4-KO mice based on Morris water maze and the Y-maze tests. The findings indicate that Prdx4-KO mice showed a lower spatial memory ability in both tests. In contrast, the results of the open field test indicated that locomotor activity is significantly increased in Prdx4-KO mice. We then performed mRNA analyses of the brains of Prdx4-KO mice and found an increased expression of genes related to the ER-associated degradation (ERAD) mechanism, which is an important protein quality control system for the maintenance of ER homeostasis. Finally, proteomic analyses of the brains of Prdx4-KO mice showed an aberrant expression in the proteins, which have been suggested to be related to calcium homeostasis and synaptogenesis in neurons. Our collective results suggest that the Prdx4 ablation perturbs oxidative protein folding in the ER, thus leading to aberrant ER homeostasis in neuronal cells, ultimately leading to impaired spatial memory formation.

Emetine and Indirubin- 3- monoxime interaction with human brain acetylcholinesterase A computational and statistical analysis.

Alzheimers disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. It is characterized by a decrease in memory, associated with the mutilation of cholinergic neurotransmission. Presently, acetylcholinesterase inhibitors have emerged as the most endorsed pharmacological medications for the symptomatic treatment of mild to moderate Alzheimers disease. This study aimed to research the molecular enzymatic inhibition of human brain acetylcholinesterase by a natural compound emetine and I3M. Molecular docking studies were used to identify superior interaction between enzyme acetylcholinesterase and ligands. Furthermore, the docked acetylcholinesterase-emetine complex was validated statistically using an analysis of variance in all tested conformers. In this interaction, H-bond, hydrophobic interaction, pi-pi, and Cation-pi interactions played a vital function in predicting the accurate conformation of the ligand that binds with the active site of acetylcholinesterase. The conformer with the lowest free energy of binding was further analyzed. The binding energy for acetylcholinesterase complex with emetine and I3M was -9.72kcalmol and -7.09kcalmol, respectively. In the current study, the prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination R2 linear 0.999), and intermolecular energy and Van der wall forces (R2 linear 0.994). These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimers disease.

Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimers disease risk.

The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimers disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- andor ε4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.

Evolution of Human-Specific Alleles Protecting Cognitive Function of Grandmothers.

The myelomonocytic receptor CD33 (Siglec-3) inhibits innate immune reactivity by extracellular V-set domain recognition of sialic acid (Sia)-containing self-associated molecular patterns (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against late-onset Alzheimers Disease (LOAD), is derived and specific to the hominin lineage. We now report multiple hominin-specific CD33 V-set domain mutations. Due to hominin-specific, fixed loss-of-function mutation in the CMAH gene, humans lack N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33. Mutational analysis and molecular dynamics (MD)-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to N-acetylneuraminic acid (Neu5Ac)-recognition. We show that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus selectively bind human CD33 (huCD33) as part of immune-evasive molecular mimicry of host SAMPs and that this binding is significantly impacted by amino acid 21 modification. In addition to LOAD-protective CD33 alleles, humans harbor derived, population-universal, cognition-protective variants at several other loci. Interestingly, 11 of 13 SNPs in these human genes (including CD33) are not shared by genomes of archaic hominins Neanderthals and Denisovans. We present a plausible evolutionary scenario to compile, correlate, and comprehend existing knowledge about huCD33-evolution and suggest that grandmothering emerged in humans.

Applications of Various Types of Nanomaterials for the Treatment of Neurological Disorders.

Neurological disorders (NDs) are recognized as one of the major health concerns globally. According to the World Health Organization (WHO), neurological disorders are one of the main causes of mortality worldwide. Neurological disorders include Alzheimers disease, Parkinsons disease, Huntingtons disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Prion disease, Brain tumor, Spinal cord injury, and Stroke. These diseases are considered incurable diseases because no specific therapies are available to cross the blood-brain barrier (BBB) and reach the brain in a significant amount for the pharmacological effect in the brain. There is a need for the development of strategies that can improve the efficacy of drugs and circumvent BBB. One of the promising approaches is the use of different types of nano-scale materials. These nano-based drugs have the ability to increase the therapeutic effect, reduce toxicity, exhibit good stability, targeted delivery, and drug loading capacity. Different types and shapes of nanomaterials have been widely used for the treatment of neurological disorders, including quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These nanoparticles have unique characteristics, including sensitivity, selectivity, and the ability to cross the BBB when used in nano-sized particles, and are widely used for imaging studies and treatment of NDs. In this review, we briefly summarized the recent literature on the use of various nanomaterials and their mechanism of action for the treatment of various types of neurological disorders.

Adherence to MIND Diet, Genetic Susceptibility, and Incident Dementia in Three US Cohorts.

Adherence to Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) may lower the risk of dementia by impacting immunity and cholesterol, which are pathways also implicated by genome-wide association studies of Alzheimers Dementia (AD). We examined whether adherence to the MIND diet could modify the association of genetic risk for AD with incident dementia. We used three ongoing US cohorts Chicago Health and Aging Project (CHAP,

Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases.

The involvement of the gut microbiota and the metabolites of colon-residing bacteria in brain disease pathogenesis has been covered in a growing number of studies, but comparative literature is scarce. To fill this gap, we explored the contribution of the microbiota-gut-brain axis to the pathophysiology of seven brain-related diseases (attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, Alzheimers disease, Parkinsons disease, major depressive disorder, and bipolar disorder). In this article, we discussed changes in bacterial abundance and the metabolic implications of these changes on disease development and progression. Our central findings indicate that, mechanistically, all seven diseases are associated with a leaky gut, neuroinflammation, and over-activated microglial cells, to which gut-residing bacteria and their metabolites are important contributors. Patients show a pro-inflammatory shift in their colon microbiota, harbouring more Gram-negative bacteria containing immune-triggering lipopolysaccharides (LPS) in their cell walls. In addition, bacteria with pro-inflammatory properties (

Assessing the Role of a Malonamide Linker in the Design of Potent Dual Inhibitors of Factor Xa and Cholinesterases.

The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to the glycinamide one, as a linker connecting the P1 benzamidine anchoring moiety to the P4 aryl group of novel selective fXa inhibitors. We carried out structure-activity relationship (SAR) studies aimed at investigating

The Influence of CB2-Receptor Ligands on the Memory-Related Responses in Connection with Cholinergic Pathways in Mice in the Passive Avoidance Test.

Role of Natural Compounds and Target Enzymes in the Treatment of Alzheimers Disease.

Alzheimers disease (AD) is a progressive neurological condition. The rising prevalence of AD necessitates the rapid development of efficient therapy options. Despite substantial study, only a few medications are capable of delaying the disease. Several substances with pharmacological activity, derived from plants, have been shown to have positive benefits for the treatment of AD by targeting various enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, and monoamine oxidases (MAOs), which are discussed as potential targets. Medicinal plants have already contributed a number of lead molecules to medicine development, with many of them currently undergoing clinical trials. A variety of medicinal plants have been shown to diminish the degenerative symptoms associated with AD, either in their raw form or as isolated compounds. The aim of this review was to provide a brief summary of AD and its current therapies, followed by a discussion of the natural compounds examined as therapeutic agents and the processes underlying the positive effects, particularly the management of AD.

Antibacterial, Antifungal, Antiviral, and Antiparasitic Activities of

Infectious diseases have always been the number one enemy threatening health and well-being. With increasing numbers of infectious diseases, growing resistance of pathogens, and declining roles of antibiotics in the treatment of infectious diseases, it is becoming increasingly difficult to treat new infectious diseases, and there is an urgent need to develop new antibiotics to change the situation. Natural products tend to exhibit many special biological properties. The genus

A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APPPS1 Mice through the GRIP1AMPA Pathway.

As a neurodegenerative disease, Alzheimers disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APPPS1 transgenic mice during this study. The cells were treated with 15 μM BG45 and the APPPS1 mice were treated with 30 mgkg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies.

Targeting Microglia in Alzheimers Disease From Molecular Mechanisms to Potential Therapeutic Targets for Small Molecules.

Alzheimers disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aβ) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aβ accumulation and tau pathology, and a chronic neuroinflammatory environment. In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aβ plaques. Nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics. In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.

A Proposal of Cognitive Intervention in Patients with Alzheimers Disease through an Assembling Game A Pilot Study.

(1) Background Alzheimers disease is an irreversible brain disease, and current treatments are aimed at fighting cognitive decline. We have explored the feasibility of a game-based intervention for people with moderate Alzheimers disease (2) Methods Six participants, five women and one man, were recruited from a day center to participate in a five-week study, which included a re- and post-evaluation with the Montreal Cognitive Assessment (MoCA) and INECO Frontal Screening (IFS) tests. Three participants were assigned to the control group and three others to the experimental one. Both groups performed a play activity consisting of assembling a pie toy. Participants in the experimental group were asked to make a pie matching a sample after a time interval. Control group participants were asked to freely assemble a pie without the matching component (3) Results Patients were shown to be motivated during such an activity during the nine sessions. The experimental group showed a significant increase in IFS scores when comparing the post- and pre-intervention assessments. No significant differences were observed in MoCA scores (4) The intervention created a social and emotional climate suitable to maintaining participants satisfaction and motivation, as well as to developing executive function while promoting positive emotions.

The Risk of Developing Alzheimers Disease and Parkinsons Disease in Patients with Inflammatory Bowel Disease A Meta-Analysis.

Recently, a growing body of research has linked gut microbiota dysbiosis to central nervous system diseases, such as Alzheimers disease (AD) and Parkinsons disease (PD), and has suggested that AD and PD pathology may take its origin from chronic inflammation in the gastrointestinal tract. Thus, this study aimed to elucidate whether inflammatory bowel disease (IBD) is associated with a higher risk of developing AD and PD as compared to the non-IBD population by conducting a meta-analysis. A thorough search of Pubmed and Embase databases was performed to identify all relevant articles. The quality of included studies was assessed using the Newcastle-Ottawa Scale. The odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed using a fixed-effect model. To assess publication bias and heterogeneity among the studies, Eggers test and LAbbé plots were used, respectively. A total of eight eligible studies were included in this meta-analysis. No significant heterogeneity or significant publication bias was detected. The risk of developing AD in IBD patients was higher than in non-IBD patients (OR 0.37 95% CI 0.14-1.00

A Metallomic Approach to Assess Associations of Plasma Metal Levels with Amnestic Mild Cognitive Impairment and Alzheimers Disease An Exploratory Study.

Alzheimers disease (AD) involves the abnormal activity of transition metals and metal ion dyshomeostasis however, the potential of trace metal biomarkers in predicting cognitive decline has not been evaluated. This study aimed to assess the potential of 36 trace elements in predicting cognitive decline in patients with amnestic mild cognitive impairment (aMCI) or AD. Participants (9 controls, 23 aMCI due to AD, and 8 AD dementia) underwent comprehensive cognitive tests, including the Mini-Mental State Examination (MMSE) and trace metal analysis. The correlations between the plasma trace element levels and annual MMSE changes during follow-up were analyzed. We found that an increase in disease severity was linked to lower plasma levels of boron (B), bismuth (Bi), thorium (Th), and uranium (U) (adjusted

Evaluating the Effect of Tideglusib-Loaded Bioactive Glass Nanoparticles as a Potential Dentine Regenerative Material.

Dental pulp treatment is the least intrusive procedure currently available for preserving the vitality of the pulp. Several studies are underway to improve the bioactivity of pulp capping materials. Tideglusib isa potent anti-inflammatory, antioxidant, and a regenerative drug developed against Alzheimers disease and has been shown to be effective in the treatment of dental cavities. However, its bioactive properties encapsulated within the nanoparticles as a component of pulp capping material are largely unknown. In this study, tideglusib-loaded bioactive glass nanoparticles were synthesized (tideglusib-BgNPs) and mixed at various concentrations into the calcium silicate cement to testits physiomechanical and bioactivitiescompared with biodentine (control). The calcium silicate cement with 10wgt% tideglusib-BgNPs showed comparable physiomechanical properties to that of biodentine. Additionally, the assessment of cytotoxicity and bioactivity (cell proliferation, wound healing, and cell migration assays) showed increased bioactivity in terms of better wound healing, increased proliferation, and better migration of human dental pulp stem cells than biodentine. These findings suggest new opportunities to use tideglusib-BgNPs in pulp therapy.

Peptidomic Approaches and Observations in Neurodegenerative Diseases.

Mass spectrometry (MS), with its immense technological developments over the last two decades, has emerged as an unavoidable technique in analyzing biomolecules such as proteins and peptides. Its multiplexing capability and explorative approach make it a valuable tool for analyzing complex clinical samples concerning biomarker research and investigating pathophysiological mechanisms. Peptides regulate various biological processes, and several of them play a critical role in many disease-related pathological conditions. One important example in neurodegenerative diseases is the accumulation of amyloid-beta peptides (Aβ) in the brain of Alzheimers disease (AD) patients. When investigating brain function and brain-related pathologies, such as neurodegenerative diseases, cerebrospinal fluid (CSF) represents the most suitable sample because of its direct contact with the brain. In this review, we evaluate publications applying peptidomics analysis to CSF samples, focusing on neurodegenerative diseases. We describe the methodology of peptidomics analysis and give an overview of the achievements of CSF peptidomics over the years. Finally, publications reporting peptides regulated in AD are discussed.

I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice.

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimers disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mgkg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.

Tau as a Biomarker of Neurodegeneration.

Less than 50 years since tau was first isolated from a porcine brain, its detection in femtolitre concentrations in biological fluids is revolutionizing the diagnosis of neurodegenerative diseases. This review highlights the molecular and technological advances that have catapulted tau from obscurity to the forefront of biomarker diagnostics. Comprehensive updates are provided describing the burgeoning clinical applications of tau as a biomarker of neurodegeneration. For the clinician, tau not only enhances diagnostic accuracy, but holds promise as a predictor of clinical progression, phenotype, and response to drug therapy. For patients living with neurodegenerative disorders, characterization of tau dysregulation could provide much-needed clarity to a notoriously murky diagnostic landscape.

Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswePS1ΔE9 Mouse Model of Alzheimers Disease.

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimers disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswePSdE1 (APPPS1) mice display age-related Aβ accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APPPS1eNOS

Oxidative Stress in Ageing and Chronic Degenerative Pathologies Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation.

Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronicpersistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, free radical scavengers, that inhibit or delay cell damage. Reinforcing the antioxidant defence system andor counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimers disease (AD) and Parkinsons disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.

A Novel Neurofilament Light Chain ELISA Validated in Patients with Alzheimers Disease, Frontotemporal Dementia, and Subjective Cognitive Decline, and the Evaluation of Candidate Proteins for Immunoassay Calibration.

Neurofilament light chain (Nf-L) is a well-known biomarker for axonal damage however, the corresponding circulating Nf-L analyte in cerebrospinal fluid (CSF) is poorly characterized. We therefore isolated new monoclonal antibodies against synthetic peptides, and these monoclonals were characterized for their specificity on brain-specific intermediate filament proteins. Two highly specific antibodies, ADx206 and ADx209, were analytically validated for CSF applications according to well-established criteria. Interestingly, using three different sources of purified Nf-L proteins, a significant impact on interpolated concentrations was observed. With a lower limit of analytical sensitivity of 100 pgmL using bovine Nf-L as the calibrator, we were able to quantify the Nf-L analyte in each sample, and these Nf-L concentrations were highly correlated to the Uman diagnostics assay (Spearman rho 0.97,

An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD).

Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADDMTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective β-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADDMTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinsons Disease, Alzheimers Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADDMTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype.

Vascular Dysfunction Is Central to Alzheimers Disease Pathogenesis in APOE e4 Carriers.

Alzheimers disease (AD) is the most common form of dementia and the leading risk factor, after age, is possession of the apolipoprotein E epsilon 4 allele (APOE4). Approximately 50% of AD patients carry one or two copies of APOE4 but the mechanisms by which it confers risk are still unknown. APOE4 carriers are reported to demonstrate changes in brain structure, cognition, and neuropathology, but findings have been inconsistent across studies. In the present study, we used multi-modal data to characterise the effects of APOE4 on the brain, to investigate whether AD pathology manifests differently in APOE4 carriers, and to determine if AD pathomechanisms are different between carriers and non-carriers. Brain structural differences in APOE4 carriers were characterised by applying machine learning to over 2000 brain MRI measurements from 33,384 non-demented UK biobank study participants. APOE4 carriers showed brain changes consistent with vascular dysfunction, such as reduced white matter integrity in posterior brain regions. The relationship between APOE4 and AD pathology was explored among the 1260 individuals from the Religious Orders Study and Memory and Aging Project (ROSMAP). APOE4 status had a greater effect on amyloid than tau load, particularly amyloid in the posterior cortical regions. APOE status was also highly correlated with cerebral amyloid angiopathy (CAA). Bulk tissue brain transcriptomic data from ROSMAP and a similar dataset from the Mount Sinai Brain Bank showed that differentially expressed genes between the dementia and non-dementia groups were enriched for vascular-related processes (e.g., angiogenesis) in APOE4 carriers only. Immune-related transcripts were more strongly correlated with AD pathology in APOE4 carriers with some transcripts such as

Cathepsin B p.Gly284Val Variant in Parkinsons Disease Pathogenesis.

Parkinsons disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B

A New Bistable Switch Model of Alzheimers Disease Pathogenesis.

We propose a model to explain the pathogenesis of Alzheimers disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease.

The Interplay between cGMP and Calcium Signaling in Alzheimers Disease.

Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimers disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca

Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System.

Heme oxygenase (HO) has both beneficial and detrimental effects via its metabolites, including carbon monoxide (CO), biliverdin or bilirubin, and ferrous iron. HO-1 is an inducible form of HO that is upregulated by oxidative stress, nitric oxide, CO, and hypoxia, whereas HO-2 is a constitutive form that regulates vascular tone and homeostasis. In brains injured by trauma, ischemia-reperfusion, or Alzheimers disease (AD), the long-term expression of HO-1 can be detected, which can lead to cytotoxic ferroptosis via iron accumulation. In contrast, the transient induction of HO-1 in the peri-injured region may have regenerative potential (e.g., angiogenesis, neurogenesis, and mitochondrial biogenesis) and neurovascular protective effects through the CO-mediated signaling pathway, the antioxidant properties of bilirubin, and the iron-mediated ferritin synthesis. In this review, we discuss the dual roles of HO-1 and its metabolites in various neurovascular diseases, including age-related macular degeneration, ischemia-reperfusion injury, traumatic brain injury, Gilberts syndrome, and AD.

Role of Impaired Mitochondrial Dynamics Processes in the Pathogenesis of Alzheimers Disease.

Mitochondrial dysfunction is now recognized as a contributing factor to neurodegenerative diseases, including Alzheimers disease (AD). Mitochondria are signaling organelles with a variety of functions ranging from energy production to the regulation of cellular metabolism, energy homeostasis, and response to stress. The successful functioning of these complex processes is critically dependent on the accuracy of mitochondrial dynamics, which includes the ability of mitochondria to change shape and position in the cell, which is necessary to maintain proper function and quality control, especially in polarized cells such as neurons. There has been much evidence to suggest that the disruption of mitochondrial dynamics may play a critical role in the pathogenesis of AD. This review highlights aspects of altered mitochondrial dynamics in AD that may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative treatment approach.

Therapeutic Potential of Allicin and Aged Garlic Extract in Alzheimers Disease.

Garlic,

Specific Cerebrospinal Fluid SerpinA1 Isoform Pattern in Alzheimers Disease.

SerpinA1 (α1-antitrypsin) is a soluble glycoprotein, the cerebrospinal fluid (CSF) isoforms of which showed disease-specific changes in neurodegenerative disorders that are still unexplored in Alz-heimers disease (AD). By means of capillary isoelectric focusing immunoassay, we investigated six serpinA1 isoforms in CSF samples of controls (

Establishing In-House Cutoffs of CSF Alzheimers Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort.

Clinical diagnosis of Alzheimers disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivitynegativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing-Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland-Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan-Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates ( We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.

Global Research on Cognitive Frailty A Bibliometric and Visual Analysis of Papers Published during 2013-2021.

This study analyzed the current status, hotspots, and emerging trends of global research on cognitive frailty, in order to provide new research ideas for researchers. Articles and reviews related to cognitive frailty, published from 2013 to 2021, were retrieved from the Web of Science Core Collection (WoSCC) database on 26 November 2021. CiteSpace 5.8.R3 was employed for data analyses. A total of 2077 publications were included. There has been a rapid growth of publications on cognitive frailty research since 2016. The United States, Italy, England, and Australia have been the leading research centers of cognitive frailty however, China has also recently focused on this topic. The National Center for Geriatrics and Gerontology, and Shimada H. were found to be the most prolific institution and author, respectively. Co-citation analysis identified 16 clusters, of which the largest was cognitive frailty. The keywords which occurred most frequently were older adult, followed by cognitive impairment, frailty, risk, dementia, prevalence, mortality, health, and Alzheimers disease. Burst keyword detection revealed a rising interest in cognitive frailty models. By analyzing these publications from recent years, this study provides a comprehensive analysis of cognitive frailty research.

Identifying the Relationship between Leisure Walking and Prevalence of Alzheimers Disease and Other Dementias.

The literature suggests that leisure walking can play an important role in preventing dementia. The purpose of the present study was to investigate the relationship between leisure walking and the prevalence of Alzheimers disease (AD) and other dementias among older adults. Using the 2020 Health and Retirement Study (HRS), 4581 responses constituted the sample for the present study. A hierarchical logit regression analysis was conducted to investigate the relationship between leisure walking and the prevalence of AD and dementia. The results show that leisure walking has been negatively associated with the prevalence of AD and other dementias-that is, they indicate that older adults who frequently engaged in leisure walking were less likely to develop AD and other dementias. This finding suggests the importance of leisure walking as a dementia prevention program for older adults.

Behavioral and Psychological Symptoms and Associated Factors in Community-Dwelling Persons at the First Time of Dementia Diagnosis.

Community-dwelling residents at potential risk of dementia and their families have difficulty detecting symptoms of dementia during an outbreak of coronavirus disease-19 (COVID-19). We explored the characteristics of behavioral and psychological symptoms of dementia (BPSD) in community-dwelling persons at the first time of dementia diagnosis and identified their associated variables. A cross-sectional study using secondary data of dementia diagnosis tests was conducted. Data were reported by professional nurses and clinicians from 355 persons at the first time of dementia diagnosis in South Korea. BPSD and their associated variables were measured with the Neuropsychiatric Inventory, the Korean version of the Consortium to Establish a Registry for Alzheimers Disease (CERAD-K) assessment handbook and electronic medical records. The most common symptoms were apathyindifference (72.1%), followed by irritabilitylability (42.8%) and depressiondysphoria (42.0%). Hierarchical regression analyses showed that the strongest factor associated with BPSD was dementia type (β -0.18, Providing information based on the study findings to families who are caring for persons at potential risk of dementia, may be able to detect dementia symptoms early and manage appropriate care.

Microglia Phenotypes in Aging and Neurodegenerative Diseases.

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimers disease (AD), and Parkinsons disease (PD). The primary focus is translational research in preclinical animal models and bulksingle-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

The Interaction of

Neurogenesis occurs in the brain during embryonic development and throughout adulthood. Neurogenesis occurs in the hippocampus and under normal conditions and persists in two regions of the brain-the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. As the critical role in neurogenesis, the neural stem cells have the capacity to differentiate into various cells and to self-renew. This process is controlled through different methods. The mammalian target of rapamycin (

Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction.

Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimers, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain. Acetylation provides a crucial connection between hepatic metabolism and mitochondrial function. Dysregulation of protein acetylation throughout the cell can alter mitochondrial function and is associated with numerous liver diseases, including non-alcoholic and alcoholic fatty liver disease, steatohepatitis, and hepatocellular carcinoma. This review introduces biochemical mechanisms of protein acetylation in the regulation of mitochondrial function and hepatic diseases and offers a viewpoint on the potential for targeted therapies.

GLP-1 Receptor Agonists in Neurodegeneration Neurovascular Unit in the Spotlight.

Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimers disease (AD) and Parkinsons disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline andor motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron-glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

Single-Cell RNA-Sequencing Astrocyte and Microglial Heterogeneity in Health and Disease.

Astrocytes and microglia are non-neuronal cells that maintain homeostasis within the central nervous system via their capacity to regulate neuronal transmission and prune synapses. Both astrocytes and microglia can undergo morphological and transcriptomic changes in response to infection with human immunodeficiency virus (HIV). While both astrocytes and microglia can be infected with HIV, HIV viral proteins in the local environment can interact with and activate these cells. Given that both astrocytes and microglia play critical roles in maintaining neuronal function, it will be critical to have an understanding of their heterogeneity and to identify genes and mechanisms that modulate their responses to HIV. Heterogeneity may include a depletion or increase in one or more astrocyte or microglial subtypes in different regions of the brain or spine as well as the gain or loss of a specific function. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool that can be used to characterise these changes within a given population. The use of this method facilitates the identification of subtypes and changes in cellular transcriptomes that develop in response to activation and various disease processes. In this review, we will examine recent studies that have used scRNA-seq to explore astrocyte and microglial heterogeneity in neurodegenerative diseases including Alzheimers disease and amyotrophic lateral sclerosis as well as in response to HIV infection. A careful review of these studies will expand our current understanding of cellular heterogeneity at homeostasis and in response to specific disease states.

Consumption of Grapes Modulates Gene Expression, Reduces Non-Alcoholic Fatty Liver Disease, and Extends Longevity in Female C57BL6J Mice Provided with a High-Fat Western-Pattern Diet.

A key objective of this study was to explore the potential of dietary grape consumption to modulate adverse effects caused by a high-fat (western-pattern) diet. Female C57BL6J mice were purchased at six-weeks-of-age and placed on a standard (semi-synthetic) diet (STD). At 11 weeks-of-age, the mice were continued on the STD or placed on the STD supplemented with 5% standardized grape powder (STD5GP), a high-fat diet (HFD), or an HFD supplemented with 5% standardized grape powder (HFD5GP). After being provided with the respective diets for 13 additional weeks, the mice were euthanized, and liver was collected for biomarker analysis, determination of genetic expression (RNA-Seq), and histopathological examination. All four dietary groups demonstrated unique genetic expression patterns. Using pathway analysis tools (GO, KEGG and Reactome), relative to the STD group, differentially expressed genes of the STD5GP group were significantly enriched in RNA, mitochondria, and protein translation related pathways, as well as drug metabolism, glutathione, detoxification, and oxidative stress associated pathways. The expression of

Health Benefits, Food Applications, and Sustainability of Microalgae-Derived N-3 PUFA.

Todays consumers are increasingly aware of the beneficial effects of n-3 PUFA in preventing, delaying, and intervening various diseases, such as coronary artery disease, hypertension, diabetes, inflammatory and autoimmune disorders, neurodegenerative diseases, depression, and many other ailments. The role of n-3 PUFA on aging and cognitive function is also one of the hot topics in basic research, product development, and clinical applications. For decades, n-3 PUFA, especially EPA and DHA, have been supplied by fish oil and seafood. With the continuous increase of global population, awareness about the health benefits of n-3 PUFA, and socioeconomic improvement worldwide, the supply chain is facing increasing challenges of insufficient production. In this regard, microalgae have been well considered as promising sources of n-3 PUFA oil to mitigate the supply shortages. The use of microalgae to produce n-3 PUFA-rich oils has been explored for over two decades and some species have already been used commercially to produce n-3 PUFA, in particular EPA- andor DHA-rich oils. In addition to n-3 PUFA, microalgae biomass contains many other high value biomolecules, which can be used in food, dietary supplement, pharmaceutical ingredient, and feedstock. The present review covers the health benefits of n-3 PUFA, EPA, and DHA, with particular attention given to the various approaches attempted in the nutritional interventions using EPA and DHA alone or combined with other nutrients and bioactive compounds towards improved health conditions in people with mild cognitive impairment and Alzheimers disease. It also covers the applications of microalgae n-3 PUFA in food and dietary supplement sectors and the economic and environmental sustainability of using microalgae as a platform for n-3 PUFA-rich oil production.

Phosphodiesterase 5 inhibitor mirodenafil ameliorates Alzheimer-like pathology and symptoms by multimodal actions.

Alzheimers disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-β (Aβ) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo3,2-dpyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties. To evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)cGMP-dependent protein kinase (PKG)cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wntβ-catenin signaling. Here, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aβ and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aβ through the modulation of the cGMPPKGCREB signaling pathway, glycogen synthase kinase 3β (GSK-3β) activity, GR transcriptional activity, and the Wntβ-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wntβ-catenin signaling. These findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMPPKGCREB pathway, GSK-3β kinase activity, GR signaling, and the Wntβ-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent.

DHCR24 Knockdown Induces Tau Hyperphosphorylation at Thr181, Ser199, Ser262, and Ser396 Sites via Activation of the Lipid Raft-Dependent RasMEKERK Signaling Pathway in C8D1A Astrocytes.

The synthetase 3β-hydroxysterol-Δ24 reductase (DHCR24) is a key regulator involved in cholesterol synthesis and homeostasis. A growing body of evidence indicates that DHCR24 is downregulated in the brain of various models of Alzheimers disease (AD), such as astrocytes isolated from AD mice. For the past decades, astrocytic tau pathology has been found in AD patients, while the origin of phosphorylated tau in astrocytes remains unknown. A previous study suggests that downregulation of DHCR24 is associated with neuronal tau hyperphosphorylation. Herein, the present study is to explore whether DHCR24 deficiency can also affect tau phosphorylation in astrocytes. Here, we showed that DHCR24 knockdown could induce tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, and Ser396 sites in C8D1A astrocytes. Meanwhile, we found that DHCR24-silencing cells had reduced the level of free cholesterol in the plasma membrane and intracellular organelles, as well as cholesterol esters. Furthermore, reduced cellular cholesterol level caused a decreased level of the caveolae-associated protein, cavin1, which disrupted lipid raftscaveolae and activated raftscaveolae-dependent RasMEKERK signaling pathway. In contrast, overexpression of DHCR24 prevented the overactivation of RasMEKERK signaling by increasing cellular cholesterol content, therefore decreasing tau hyperphosphorylation in C8D1A astrocytes. Herein, we firstly found that DHCR24 knockdown can lead to tau hyperphosphorylation in the astrocyte itself by activating lipid raft-dependent RasMEKERK signaling, which might contribute to the pathogenesis of AD and other degenerative tauopathies.

Silent Brain Infarction, Delirium, and Cognition in Three Invasive Cardiovascular Procedures a Systematic Review.

Silent brain infarctions (SBIs) are brain lesions noted on neuroimaging that are not associated with clinical symptoms. SBIs are associated with a number of vascular risk factors and are common following invasive cardiovascular procedures such as atrial fibrillation (AF) ablation, coronary artery bypass graft (CABG), and transcatheter aortic valve replacement (TAVR). Although not eliciting signs of clinical stroke, SBIs are associated with increased frailty, and motor and mood features. Less is known, however, about the relationship between SBI, cognition, and delirium following invasive cardiac procedures and most investigations into these relationships have been reported in large-scale epidemiological studies. In the current paper, we conducted a systematic review to evaluate evidence of a relationship between SBI, delirium, and cognitive decline following CABG, AF ablation, and TAVR. Twenty studies met inclusion criteria. In general, our review identified conflicting results for each cardiac procedure, with some studies suggesting a relationship between SBI, cognitive impairment, and delirium, whereas others showed no relationship between SBI, cognitive impairment, and delirium. Potential reasons for this discrepancy as well as suggestions for future research are discussed.

Access to Disease-Modifying Alzheimers Therapies Addressing Possible Challenges Using Innovative Payment Models.

Aduhelm is the first approved disease-modifying therapies (DMT) for Alzheimer disease (AD). Nevertheless, under current payment models, AD DMTs-especially because they treat broader populations-will pose challenges to patient access since costs may accrue sooner than benefits do. New payment approaches may be needed to address this difference in timing. We use the Future Elderly Model that draws on nationally representative data sets such as the Health and Retirement Study to estimate the potential benefits because of hypothetical AD DMTs in 4 stylized treatment scenarios for patients with mild cognitive impairment or mild AD, and develop a payment model to estimate the accrual of net costs and benefits to private and public payers. The modeled AD DMTs result in clinical benefit of 0.30 to 0.55 quality-adjusted life-years gained per patient in the baseline treatment scenario and 0.13 to 0.24 quality-adjusted life-years gained per patient in the least optimistic scenario. Private payers may observe a net loss in patients at the age of 61 to 65 years under the status quo (payment upon treatment). Constant and deferred installment payment models resolve this issue. Innovative payment solutions, such as installment payments, may be required to address misaligned incentives that AD DMTs may create among patients younger than the age of 65 years and may help address concerns about the timing and magnitude of costs and benefits accrued to private payers.

Temperature-dependent self-assembly of biofilaments during red blood cell sickling.

Molecular self-assembly plays a vital role in various biological functions. However, when aberrant molecules self-assemble to form large aggregates, it can give rise to various diseases. For example, sickle cell disease and Alzheimers disease are caused by self-assembled hemoglobin fibers and amyloid plaques, respectively. Here, we study the assembly kinetics of such fibers using kinetic Monte Carlo simulation. We focus on the initial lag time of these highly stochastic processes, during which self-assembly is very slow. The lag time distributions turn out to be similar for two very different regimes of polymerization, namely, (a) when polymerization is slow and depolymerization is fast and (b) the opposite case, when polymerization is fast and depolymerization is slow. Using temperature-dependent on- and off-rates for hemoglobin fiber growth, reported in recent in vitro experiments, we show that the mean lag time can exhibit non-monotonic behavior with respect to the change in temperature.

DYRK1A regulates the bidirectional axonal transport of APP in human-derived neurons.

Polymorphisms of apolipoprotein E in the Afro-descendant population of Buenaventura, Colombia.

To estimate the frequency distribution, both allelic and genotypic, of the APOE gene in the Afro-descendant population of Buenaventura, Colombia. Three hundred and forty-eight Afro-descendant individuals were analysed and the APOE locus was genotyped by PCR-RFLP. The allelic and genotypic frequencies were established by direct counting and the Hardy-Weinberg equilibrium was evaluated through χ The following allelic frequencies were observed E3, 70.8% E4, 21.4%, and E2, 7.8%. The genotypic frequencies were E3E3, 51.1% E3E4, 27.3% E2E3, 12.1% E4E4, 6% E2E4, 3.5%, and E2E2, 0%. The entire examined population was found in Hardy-Weinberg equilibrium (P.074), and significant differences were found in the allele E4 when comparing this population with the Amerindian and mestizo populations of Bogotá, Quindío, Centro-Oriente, Valle del Cauca, Barranquilla and Medellín (P≤ 0.0345). The allelic frequencies observed in this study were significantly different from the frequencies reported in other Colombian populations. The high representativeness of the E4 and E2 alleles validates the hypothesis that there are micro-evolutionary processes that have been acting on their frequencies and could be associated with susceptibility to neuropsychiatric diseases such as Alzheimers disease, metabolic alterations of fats andor coronary artery disease.

ADVANCE-C A Qualitative Study of Experiences Caring for Nursing Home Residents with Advanced Dementia During the COVID-19 Pandemic.

Assessment of Disparities and Variation for Alzheimers disease Nursing home Care at End of life (ADVANCE) is a multisite qualitative study of regionally diverse Nursing homes (NHs N 14) providing varied intensity of advanced dementia care. ADVANCE-C explored the experiences of NH staff and proxies during the COVID-19 pandemic. Data collection occurred in five of the ADVANCE facilities located in Georgia (N 3) and New York (N 2). Semistructured qualitative interviews with NH staff (N 38) and proxies of advanced dementia residents (N 7) were conducted. Framework analyses explored five staff domains care processes, decision making, organizational resources, vaccinations, and personal experience, and five proxy domains connecting with residents, NH response, communicating with NH, decision making, and personal impact of the pandemic. Staff mentioned difficulties implementing infection control policies specifically for advanced dementia residents. Staff reported trust between the facility and proxies as critical in making decisions during the pandemic. All staff participants spoke about coming together to address persistent staffing shortages. Proxies described their role as an emotional rollercoaster, emphasizing how hard it was being separate from their loved ones. The accommodations made for NH residents were not beneficial for those with advanced dementia. The majority of proxies felt NH staff were doing their best and expressed deep appreciation for their care. Caring for advanced dementia residents during the COVID-19 pandemic had unique challenges for both staff and proxies. Strategies for similar future crises should strive to balance best practices to contain the virus while maintaining family connections and person-centered care.

Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimers disease.

Microglia are critical in brain development and Alzheimers disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS microglial functions and prevent senescence.

The association of apolipoprotein E (ApoE) genotype and cognitive outcomes in multiple sclerosis a systematic review and meta-analysis.

Multiple sclerosis (MS) is a neuroinflammatory disorder commonly seen in young female adults. Cognitive impairment is one of the widespread symptoms of MS. In recent years multiple studies sought the possible risk factors for MS-related cognitive deficit. Apolipoprotein E (ApoE) genotype is one of the genetic factors which correlated significantly with cognitive status and it is a well-known risk factor for Alzheimers Disease. In this systematic review and meta-analysis, we collected the current evidence to evaluate the association between the ApoE genotype and the cognitive outcomes in patients with MS. Results of searches through Medline via PubMed, Scopus, and ISI web of science, as well as hand searching, were screened in the titleabstract and full-text stages. English observational studies in which the association between ApoE and cognitive outcomes, in patients with MS were included in this systematic review. Animal studies, conference abstracts, reviews, clinical trials, case reports, letters and withdrawn studies, were not included. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools and the meta-analysis was conducted with Comprehensive Meta-Analysis (CMA.2) software. The numbers of patients with impairment in both ApoE4 and ApoE4- groups were utilized for the calculation of the odds ratios (ORs) with 95% confidence intervals (CI) and a 0.05 level of significance for p-value. Out of 224 results of searching, 13 studies met the eligibility criteria and were included in our systematic review, and 5 of them were included in the quantitative synthesis. Eleven studies assessed the cognitive status of patients with MS in two groups of ApoE4 and ApoE4- while 2 rests, reported the rate of ApoE4 patients in cognitively impaired and non-impaired groups. The phenotype of MS was only Relapsing-remitting multiple sclerosis (RRMS) in 3 studies and in the other 10 studies, it was a mixture of RRMS, clinically isolated syndrome (CIS), and progressive MS. Most of the reports did not find a significant association between ApoE genotype and cognitive outcomes in patients with MS. Contrary to the expectations, patients in ApoE4- group were more likely to have impairment in Judgment of Line Orientation (JLO) (OR 0.405 95% CI 0.173 to 0.949, p-value0.038), while ApoE4 patients had more rate of impairment in SRT (OR1.901 95%CI 1.237 to 2.920 p-value0.003). Appropriate identifying and dealing with cofounding factors were the most common source of bias in our included studies. ApoE may have a domain-specific association with cognitive impairment in MS patients. ApoE4 patients had more delayed responses to stimuli, but the rate of impaired visuospatial perception is lower in these patients. Based on the current evidence, there is a doubt about the clinical significance of this association.

Electroencephalographic signatures of dogs with presumptive diagnosis of canine cognitive dysfunction.

Canine cognitive dysfunction (CCD) is a highly prevalent neurodegenerative disease considered the canine analog of early Alzheimers disease (AD). Unfortunately, CCD cannot be cured. However, early therapeutic interventions can slow the progression of cognitive decline and improve quality of life of the patients therefore, early diagnosis is ideal. In humans, electroencephalogram (EEG) findings specific to AD have been described, and some of them have successfully detect early stages of the disease. In this study we characterized the EEG correlates of CCD, and we compared them with the EEGs of healthy aging dogs and dogs at risk of developing CCD. EEG recordings were performed in 25 senior dogs during wakefulness. Dogs were categorized in normal, at risk of CCD or with CCD according to their score in the Rofina questionnaire. We demonstrated that, quantitative EEG can detect differences between normal dogs and dogs with CCD. Dogs with CCD experience a reduction in beta and gamma interhemispheric coherence, and higher Joint Lempel Ziv complexity. Dogs at risk of developing CCD, had higher alpha power and interhemispheric coherence, making these features potential markers of early stages of the disease. These results demonstrate that quantitative EEG analysis could aid the diagnosis of CCD, and reinforce the CCD as a translational model of early AD.

Designing Protease-Triggered Protein Cages.

Proteins that self-assemble into enclosed polyhedral cages, both naturally and by design, are garnering attention for their prospective utility in the fields of medicine and biotechnology. Notably, their potential for encapsulation and surface display are attractive for experiments that require protection and targeted delivery of cargo. The ability to control their opening or disassembly would greatly advance the development of protein nanocages into widespread molecular tools. Toward the development of protein cages that disassemble in a systematic manner and in response to biologically relevant stimuli, here we demonstrate a modular protein cage system that is opened by highly sequence-specific proteases, based on sequence insertions at strategically chosen loop positions in the protein cage subunits. We probed the generality of the approach in the context of protein cages built using the two prevailing methods of construction genetic fusion between oligomeric components and (non-covalent) computational interface design between oligomeric components. Our results suggest that the former type of cage may be more amenable than the latter for endowing proteolytically controlled disassembly. We show that a successfully designed cage system, based on oligomeric fusion, is modular with regard to its triggering protease. One version of the cage is targeted by an asparagine protease implicated in cancer and Alzheimers disease, whereas the second version is responsive to the blood-clotting protease, thrombin. The approach demonstrated here should guide future efforts to develop therapeutic vectors to treat disease states where protease induction or mis-regulation occurs.

Functionalized Allopurinols Targeting Amyloid-Binding Alcohol Dehydrogenase Rescue Aβ-Induced Mitochondrial Dysfunction.

Alzheimers disease (AD) is the most common dementia affecting one in nine people over 65. Only a handful of small-molecule drugs and the anti-β amyloid (Aβ) antibody aducanumab are approved to treat AD. However, they only serve to reduce symptoms of advanced disease. Novel treatments administered early in disease progression before the accumulation of Aβ and tau reaches the threshold where neuroinflammation is triggered and irreversible neuronal damage occurs are more likely to provide effective therapy. There is a growing body of evidence implying that mitochondrial dysfunction occurs at an early stage of AD pathology. The mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) binds to Aβ potentiating toxicity. Moreover, ABAD has been shown to be overexpressed in the same areas of the brain most affected by AD. Inhibiting the Aβ-ABAD protein-protein interaction without adversely affecting normal enzyme turnover is hypothesized to be a potential treatment strategy for AD. Herein, we conduct structure-activity relationship studies across a series of functionalized allopurinol derivatives to determine their ability to inhibit Aβ-mediated reduction of estradiol production from ABAD. The lead compound resulting from these studies possesses potent activity with no toxicity up to 100 μM, and demonstrates an ability to rescue defective mitochondrial metabolism in human SH-SY5Y cells and rescue both defective mitochondrial metabolism and morphology ex vivo in primary 5XFAD AD mouse model neurons.

Effects of antidiabetic agents on Alzheimers disease biomarkers in experimentally induced hyperglycemic rat model by streptozocin.

Alzheimers disease is the most common cause of dementia in the elderly population. It is characterized by the accumulation of amyloid β and intraneuronal neurofibrillary tangles in the brain. Increasing evidence shows that the disturbance of insulin signalling in the brain may contribute to the pathophysiology of Alzheimers disease. In type 1 diabetes, these disruptions are caused by hypoinsulinemia, but in type 2 diabetes, they are caused by insulin resistance and decreased insulin secretion. Multiple studies have shown that diabetes is connected with an increased risk of acquiring Alzheimers disease. The aim of this study was to investigate the impact of anti-diabetic agents on Alzheimers disease progression and the levels of Alzheimers biomarkers in a hyperglycaemic rat model, which was induced by intraperitoneal injection of streptozocin to produce insulin-deficient diabetes. Thirty-six male Wistar albino rats were allocated into six groups of six rats each. Group I was the negative control group. Intraperitoneal injections of streptozocin (42mgkg) were used once for the five experimental groups. Group II served as the positive control group. The rats in Groups III, IV, V, and VI received metformin (300mgkg), donepezil (10mgkg), insulin glargine (3 unitanimal), and glibenclamide (10mgkg), respectively, for 21 days. Inducing hyperglycaemia in rats significantly increased the levels of serum glucose, haemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein, interleukin 6, tumour necrosis factor alpha, amyloid β 42, total plasma tau, and neurofilament light. A significant increase was also found in brain amyloid β 42, nitric oxide, acetylcholinesterase, malondialdehyde, β secretase, and phosphorylated microtubule-associated protein tau. The greatest statistically significant reductions in serum glucose, haemoglobin A1c, triglycerides, amyloid β 42, total plasma tau, brain amyloid β 42, acetylcholinesterase, and malondialdehyde were observed in rats treated with metformin. In contrast, rats treated with donepezil demonstrated the greatest statistically significant reduction in serum tumour necrosis factor alpha, brain nitric oxide, and β secretase. The levels of neurofilament light and phosphorylated microtubule-associated protein tau in the brains of rats treated with insulin glargine were significantly lower than the other treatment groups. The total cholesterol and low-density lipoprotein levels in rats treated with glibenclamide exhibited the most statistically significant reductions of all the treatment groups. Metformin and donepezil, when administered at appropriate doses, were shown to successfully lower most plasma and brain biomarkers, including glucose, triglycerides, tumour necrosis factor alpha, amyloid β 42, nitric oxide, acetylcholinesterase, malondialdehyde, and β secretase in rats suffering from Diabetes Mellitus. As a result of this research, we suggest that metformin, either alone or in conjunction with donepezil, might be an excellent drug of choice for neuro-regeneration and risk reduction in Alzheimers like disease.

Dementia risk and dynamic response to exercise A non-randomized clinical trial.

Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the Apolipoprotein epsilon 4 (APOE4) allele, a genetic risk factor for developing Alzheimers. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. Sixty-two older adults (73±5 years old, 41 female 67%) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). Genotyping failed in one individual (n 23 APOE4 carriers and n 38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellum across both groups. Among high inter-individual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study provide an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimers disease. Dementia Risk and Dynamic Response to Exercise (DYNAMIC) Identifier NCT04009629.

Icariin A Potential Neuroprotective Agent in Alzheimers Disease and Parkinsons Disease.

Alzheimers disease (AD) and Parkinsons disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

Demographic and clinical profile of residents living with dementia and depressive symptoms in Australian private residential aged care Data from the Music Interventions for Dementia and Depression in ELderly care (MIDDEL) cluster-randomised controlled trial.

1) To describe the demographic and clinical characteristics of residents with dementia and depressive symptoms in the Australian private residential aged care (RAC) context and 2) to investigate the association between neuropsychiatric symptoms, depression and quality of life and their interactions with dementia severity. This study examined the baseline demographic and clinical data from the Australian arm of the Music Interventions for Dementia and Depression in ELderly care (MIDDEL) study, a multinational, cluster-randomised controlled trial. Demographic characteristics, neuropsychiatric symptoms, depression, quality of life and dementia severity were collected in 330 residents of 12 private RAC facilities across Melbourne, Australia. Descriptive statistics, the Kruskal-Wallis test and the Pearson Χ Residents mean age was 86.5 years, 69% were female, and 44.2% had severe dementia. There were no significant differences between the dementia severity groups on age, sex and education. Residents with severe dementia were more likely to have a diagnosis of Alzheimers disease (40.3%) and be born overseas (46.8%). Higher levels of neuropsychiatric symptoms, distress and depressive symptoms, and lower quality of life were associated with more severe dementia. The findings from our study highlight the diverse and complex care needs of people living with dementia in the Australian private RAC setting, which can be used to inform targeted, person-centred dementia care planning, staff training and allocation of resources.

Dual functional amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles for the monitoring and inhibition of insulin amyloid fibrillation based on carbohydrate-protein interactions.

Amyloid-related diseases, such as Alzheimers disease, are all considered to be related to the deposition of amyloid fibrils in the body. Insulin is a protein hormone that easily undergoes aggregation and fibrillation to form more toxic amyloid-like fibrils. So far, it is still challenging to develop a new protocol to study the

A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model.

Alzheimers disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age-dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P-Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage-dependent anion channel 1 (VDAC1) protein on mitophagyautophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimers disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1

The Role of Mesenchymal Stem Cells in Regulating Astrocytes-Related Synapse Dysfunction in Early Alzheimers Disease.

Alzheimers disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-β (Aβ) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aβ oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aβ metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aβ metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.

Inter-organellar Communication in Parkinsons and Alzheimers Disease Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites.

Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinsons disease (PD) and Alzheimers disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.

Evaluating the Causal Effects of Gestational Diabetes Mellitus, Heart Disease, and High Body Mass Index on Maternal Alzheimers Disease and Dementia Multivariable Mendelian Randomization.

Relationship Between Arterial Stiffness Index, Pulse Pressure, and Magnetic Resonance Imaging Markers of White Matter Integrity A UK Biobank Study.

Alzheimers disease and dementia in general constitute one of the major public health problems of the 21st century. Research in arterial stiffness and pulse pressure (PP) play an important role in the quest to reduce the risk of developing dementia through controlling modifiable risk factors. The aim of the study is to investigate the association between peripheral PP, arterial stiffness index (ASI) and brain integrity, and to discover if ASI is a better predictor of white matter integrity than peripheral PP. 17,984 participants 63.09 ± 7.31 from the UK Biobank were used for this study. ASI was estimated using infrared light (photoplethysmography) and peripheral PP was calculated by subtracting the diastolic from the systolic brachial blood pressure value. Measure of fractional anisotropy (FA) was obtained from diffusion imaging to estimate white matter microstructural integrity. White matter hyperintensities were segmented from the combined T1 and T2-weighted FLAIR images as a measure of irreversible white matter damage. An important finding is that peripheral PP better predicts white matter integrity when compared to ASI. This finding is consistent until 75 years old. Interestingly, no significant relationship is found between either peripheral PP or ASI and white matter integrity after 75 years old. These results suggest that ASI from plethysmography should not be used to estimate cerebrovascular integrity in older adults and further question the relationship between arterial stiffness, blood pressure, and white matter damage after the age of 75 years old.

Brain Structural and Functional Changes in Cognitive Impairment Due to Alzheimers Disease.

Cognitive neuropsychology seeks a potential alignment between structural and functional brain features to explain physiological or pathological processes, such as Alzheimers disease (AD). Several structural and functional brain changes occurring during the disease, including cognitive impairment, are found at the end of the patients life, but we need to know more about what happens before its onset. In order to do that, we need earlier biomarkers at preclinical stages, defined by those biomarkers, to prevent the cognitive impairment. In this minireview, we have tried to describe the structural and functional changes found at different stages during AD, focusing on those features taking place before clinical diagnosis.

Plasma biomarkers for prognosis of cognitive decline in patients with mild cognitive impairment.

Plasma-based biomarkers present a promising approach in the research and clinical practice of Alzheimers disease as they are inexpensive, accessible and minimally invasive. In particular, prognostic biomarkers of cognitive decline may aid in planning and management of clinical care. Although recent studies have demonstrated the prognostic utility of plasma biomarkers of Alzheimer pathology or neurodegeneration, such as pTau-181 and NF-L, whether other plasma biomarkers can further improve prediction of cognitive decline is undetermined. We conducted an observational cohort study to determine the prognostic utility of plasma biomarkers in predicting progression to dementia for individuals presenting with mild cognitive impairment due to probable Alzheimers disease. We used the Olink™ Proximity Extension Assay technology to measure the level of 460 circulating proteins in banked plasma samples of all participants. We used a discovery data set comprised 60 individuals with mild cognitive impairment (30 progressors and 30 stable) and a validation data set consisting of 21 stable and 21 progressors. We developed a machine learning model to distinguish progressors from stable and used 44 proteins with significantly different plasma levels in progressors versus stable along with age, sex, education and baseline cognition as candidate features. A model with age, education, APOE genotype, baseline cognition, plasma pTau-181 and 12 plasma Olink protein biomarker levels was able to distinguish progressors from stable with 86.7% accuracy (mean area under the curve 0.88). In the validation data set, the model accuracy was 78.6%. The Olink proteins selected by the model included those associated with vascular injury and neuroinflammation (e.g. IL-8, IL-17A, TIMP-4, MMP7). In addition, to compare these prognostic biomarkers to those that are altered in Alzheimers disease or other types of dementia relative to controls, we analyzed samples from 20 individuals with Alzheimer, 30 with non-Alzheimer dementias and 34 with normal cognition. The proteins NF-L and PTP-1B were significantly higher in both Alzheimer and non-Alzheimer dementias compared with cognitively normal individuals. Interestingly, the prognostic markers of decline at the mild cognitive impairment stage did not overlap with those that differed between dementia and control cases. In summary, our findings suggest that plasma biomarkers of inflammation and vascular injury are associated with cognitive decline. Developing a plasma biomarker profile could aid in prognostic deliberations and identify individuals at higher risk of dementia in clinical practice.

An Optimized Hyperparameter of Convolutional Neural Network Algorithm for Bug Severity Prediction in Alzheimers-Based IoT System.

Softwares are involved in all aspects of healthcare, such as booking appointments to software systems that are used for treatment and care of patients. Many vendors and consultants develop high quality software healthcare systems such as hospital management systems, medical electronic systems, and middle-ware softwares in medical devices. Internet of Things (IoT) medical devices are gaining attention and facilitate the people with new technology. The health condition of the patients are monitored by the IoT devices using sensors, specifically brain diseases such as Alzheimer, Parkinsons, and Traumatic brain injury. Embedded software is present in IoT medical devices and the complexity of software increases day-by-day with the increase in the number and complexity of bugs in the devices. Bugs present in IoT medical devices can have severe consequences such as inaccurate records, circulatory suffering, and death in some cases along with delay in handling patients. There is a need to predict the impact of bugs (severe or nonsevere), especially in case of IoT medical devices due to their critical nature. This research proposes a hybrid bug severity prediction model using convolution neural network (CNN) and Harris Hawk optimization (HHO) based on an optimized hyperparameter of CNN with HHO. The dataset is created, that consists of the bugs present in healthcare systems and IoT medical devices, which is used for evaluation of the proposed model. A preprocessing technique on textual dataset is applied along with a feature extraction technique for CNN embedding layer. In HHO, we define the hyperparameter values of Batch Size, Learning Rate, Activation Function, Optimizer Parameters, and Kernel Initializers, before training the model. Hybrid model CNN-HHO is applied, and a 10-fold cross validation is performed for evaluation. Results indicate an accuracy of 96.21% with the proposed model.

Overproduction of Nitric oxide (NO) and many other pro-inflammatory mediators are responsible for many pathological disorders in humans, including Alzheimers disease (AD). In this study, active fractions isolated from

Mouse Models of Alzheimers Disease.

Alzheimers disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles, which comprise abnormally aggregated β-amyloid peptide (Aβ) and hyperphosphorylated tau protein. To develop preventive, diagnostic, and therapeutic strategies for AD, it is essential to establish animal models that recapitulate the pathophysiological process of AD. In this review, we will summarize the advantages and limitations of various mouse models of AD, including transgenic, knock-in, and injection models based on Aβ and tau. We will also discuss other mouse models based on neuroinflammation because recent genetic studies have suggested that microglia are crucial in the pathogenesis of AD. Although each mouse model has its advantages and disadvantages, further research on AD pathobiology will lead to the establishment of more accurate mouse models, and accelerate the development of innovative therapeutics.

Molecular mechanisms of amyloid formation in living systems.

Fibrillar protein aggregation is a hallmark of a variety of human diseases. Examples include the deposition of amyloid-β and tau in Alzheimers disease, and that of α-synuclein in Parkinsons disease. The molecular mechanisms by which soluble proteins form amyloid fibrils have been extensively studied in the test tube. These investigations have revealed the microscopic steps underlying amyloid formation, and the role of factors such as chaperones that modulate these processes. This perspective explores the question to what extent the mechanisms of amyloid formation elucidated

Repurposing of intestinal defensins as multi-target, dual-function amyloid inhibitors

Amyloid formation and microbial infection are the two common pathological causes of neurogenerative diseases, including Alzheimers disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While significant efforts have been made to develop different prevention strategies and preclinical hits for these diseases, conventional design strategies of amyloid inhibitors are mostly limited to either a single prevention mechanism (amyloid cascade

Discovering Gene Signature Shared by Prostate Cancer and Neurodegenerative Diseases Based on the Bioinformatics Approach.

Prostate cancer (PCa) is one of the highest frequent malignant tumors with very complicated pathogenesis. Genes of neurodegenerative diseases can influence tumor progression. But its role in the progression of PCa remains unclear. The purpose of the present academic work was to identify significant genes with poor outcome and their underlying mechanism. The GSE70768, GSE88808, and GSE134051 datasets were downloaded to screen the differentially expressed genes (DEGs). The DEG screening criteria were as follows A total of 263 co-DEGs were identified from the three datasets. GO analysis showed that co-DEGs were mainly involved in muscle contraction and blood circulation regulation. The top ten key genes were ACTG2, APOE, F5, CALD1, MYH11, MYL9, MYLK, TPM1, TPM2, and CALM1. GEPIA2 analysis showed that APOE, MYH11, and MYLK differ dramatically between tumor and normal tissues. These key genes are related to disease-free survival (DFS) in PCa. APOE was the intersection gene between key genes and Alzheimer-related genes. The neurodegenerative gene APOE may be a potential prognostic and diagnostic biomarker for PCa.